Recent Advances in the Development of Indazole

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DOI: 10.1002/cmdc.201800253

Recent Advances in the Development of Indazole-based Anticancer Agents Jinyun Dong, Qijing Zhang, Zengtao Wang, Guang Huang,* and Shaoshun Li*[a] Cancer is one of the leading causes of human mortality globally; therefore, intensive efforts have been made to seek new active drugs with improved anticancer efficacy. Indazole-containing derivatives are endowed with a broad range of biological properties, including anti-inflammatory, antimicrobial, antiHIV, antihypertensive, and anticancer activities. In recent years, the development of anticancer drugs has given rise to a wide

range of indazole derivatives, some of which exhibit outstanding activity against various tumor types. The aim of this review is to outline recent developments concerning the anticancer activity of indazole derivatives, as well as to summarize the design strategies and structure–activity relationships of these compounds.

1. Introduction Cancer is one of the leading causes of human mortality globally; thus, the world has been paying close attention to its treatment. Compared with radiotherapy and biological therapy, chemotherapy remains the backbone of current treatment. Nevertheless, a broad array of these drugs is limited by a narrow therapeutic index and frequently acquired resistance. Consequently, the development of novel anticancer drugs with high efficiency and low toxicity is still urgently needed. Nitrogen-containing heterocycles are pharmacologically important scaffolds, and they are widely present in numerous commercially available drugs. As a crucial family of nitrogencontaining heterocycles, the structurally diverse indazole analogues have received enormous attention in the past, as well as in recent years, because of their varieties of biological properties, such as anti-inflammatory, antimicrobial, anti-HIV, antihypertensive, and anticancer activities.[1–7] More importantly, some indazole-based therapeutic agents, like pazopanib, axitinib, and niraparib have been approved for the treatment of cancers. Structurally, indazole, also called benzpyrazole or isoindazone, is an aromatic heterocyclic molecule in which a benzene ring is fused with a pyrazole ring. It exists in three tautomeric forms: 1H-indazole, 2H-indazole, and 3H-indazole (Figure 1). 1H-Indazole and its derivatives are usually thermodynamically more stable than the corresponding 2H- or 3Hforms and are therefore the predominant tautomers.[8] There is evidence that the indazole tautomer identity has an influence on biological properties.[9]

[a] Dr. J. Dong, Dr. Q. Zhang, Z. Wang, Dr. G. Huang, Prof. S. Li School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai (China) E-mail: [email protected] [email protected] The ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/cmdc.201800253.

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Figure 1. Tautomers of indazole.

Pharmacologically and structurally diverse indazole analogues have been the subject of new publications. Correspondingly, there are several reviews focused primarily on the synthetic methods to build the indazole skeleton and the broad range of bioactivities of indazole derivatives that can be found in the literature.[10, 11] This work has contributed significantly to the general scientific understanding of these compounds. However, a vast number of novel indazole-containing molecules endowed with antineoplastic activity have been reported recently, and some are currently progressing into clinical trials. This reflects the importance, as well as research intensity, of this field, and an up-to-date review is highly merited. Herein, we attempted to describe the design strategies and progress made from 2013 to the beginning of 2018 in the development of indazole-based anticancer agents. The indazole derivatives discussed in this minireview are grouped on the basis of their biomolecular targets. We hope this work will provide useful clues for rational design of indazole-containing derivatives as more potent antitumor candidates.

2. Indazole derivatives as receptor tyrosine kinase inhibitors The human receptor tyrosine kinase (RTK) family consists of 58 proteins divided into 20 subfamilies. These RTKs play a pivotal role in regulating cell proliferation, differentiation, survival, apoptosis, adhesion, and migration. However, hyperactivation of RTKs could result in the development of a number of cancers. As a result, inhibition of RTK activity is becoming a common strategy for cancer therapy. Recently, the development of indazole derivatives targeting epidermal growth factor

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Minireviews receptor (EGFR), fibroblast growth factor receptors (FGFRs), and vascular endothelial growth factor receptors (VEGFRs) has been widely reported. 2.1. Inhibition of EGFR The ErbB family consists of four members: EGFR (ErbB1/HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).[12, 13] Among these, EGFR is the currently the most extensively studied molecular target in anticancer research. Dysregulation of EGFR, caused by point mutation L858R or exon 19 deletion (DGlu 746–Ala 750), can aberrantly trigger EGFR-dependent pathways, which contribute to the development and malignancy of a subset of major cancer types, such as non-small-cell lung cancer (NSCLC), prostate, breast, stomach, and ovarian cancers.[14–18] Although the reversible first-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have achieved dramatic initial clinical responses, patients suffer from dramatic relapse in a few months as a result of secondary mutations, especially T790M mutation. This stimulates the development of second-generation irreversible TKIs, such as neratinib, dacomitinib, and afatinib. They can potently block T790M resistance mutation by formation of a covalent bond between the Michael acceptor and Cys 797. Unfortunately, some severe side effects are observed in clinic due to the

narrow selectivity window between wild-type EGFR and mutants. Starting from hit compound 1, which emerged from a phenotypic screen of 1500 compounds against 80 NSCLC cell lines, Engel et al. presented a structure-guided development of several irreversible inhibitors that could selectively target the L858R/T790M mutant form of EGFR (Figure 2).[19] Subsequent synthesis of a large number of analogues led to the discovery of indazole analogue 2, which was characterized as the most active compound, with IC50 values toward L858R/T790M, L858R, and wild-type EGFR of 0.07, 0.50 and 1.70 mm, respectively. In particular, this compound showed a strikingly increased inhibitory effect on the drug-resistant mutant of EGFR. Structurally, as a hinge-binding element, the indazole scaffold provided suitable chemical and spatial features to accommodate the space between the hinge region and the gatekeeper residues, without suffering from steric clashes with the methionine side chain. Additionally, the indazole moiety played a prominent role in forming hydrogen bonds with the peptide backbone of residues Glu 339 and Met 341. The phenyl part of the indazole furnished a favorable hydrophobic gatekeeper interaction, resulting in improved protein–ligand interactions. As a linker, phenyl ether was equipped with an electrophilic acrylamide that could undergo a Michael addition to form a covalent bond to Cys 797 of EGFR-T790M. It should be noted that

Figure 2. Discovery of indazole derivatives 2–7 as EGFR inhibitors. Reproduced with permission from Ref. [19]. Copyright American Chemical Society, 2015.

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Minireviews the acrylamide moiety is a favored electrophile for this scaffold with regard to its size, reactivity, and orientation. 1-Methylpiperazine as a solubilizing group was appended to the 6-position of the pyrimidine with the aim of restricting the structural flexibility. However, this promising activity of 2 in enzymatic assays did not translate into cellular activity. It showed moderate inhibitory effect effects on the activating cell line HCC827 (DGlu 746–Ala 750) and drug-resistant H1975 cells (harboring L858R/T790M) (GI50 = 2.5 and 9.8 mm, respectively), being equipotent to the wild-type cell line A431 (GI50 = 8.6 mm). This phenomenon was ascribed to poor overall absorption caused by a high efflux rate. In light of the poor cellular potency and slow rate of covalent bond formation of compound 2, the research group continued to prepare a set of indazole-based derivatives by reducing molecular flexibility and optimizing spatial arrangement of the acrylamide to covalently target the reactive cysteine in the binding site (Figure 2).[20] Aromatic extensions in the 6- or 5-positions of the indazole were aimed to extend toward the binding site or interact with the methionine gatekeeper. A tertiary amine side chain was introduced to increase solubility. Among these derivatives, compounds bearing substituents on the 6position of the indazole ring (such as 3 and 4) exhibited striking selectivity over wild-type EGFR, being active against the L858R/T790M double-mutated EGFR with IC50 values below 5 nm biochemically and below 500 nm against the corresponding cells. It is interesting to note that compound 5, with a flexible secondary amine-bridged meta-fluorobenzene moiety, was found to be the most potent EGFR inhibitor, with IC50 values in the sub-nanomolar range against all of the forms tested biochemically and cellular activity below 200 nm in the drug-resistant H1975 cell line. In addition, compounds 6 and 7, carrying 2-naphthyl and para-fluorobenzene moieties in the 5-position, respectively, displayed robust inhibition of double-mutated EGFR, in addition to having a good selectivity profile. As expected, a kinetic assay disclosed fast covalent bond formation rates for compounds 3 and 6 binding with EGFR-L858R/T790M. Of particular note, C797S mutation-mediated resistance to the third-generation covalent inhibitor AZD9291 has also been reported, which encouraged chemists to seek T790M inhibitors that did not depend on a covalent interaction with Cys 797.[21, 22] Hanan et al. identified 4-aminoindazolyldihydrofuro[3,4-d]pyrimidine (8) as a potent TMLR (T790M/L858R) inhibitor, with a Ki value of 2 nm and moderate activity in a cellbased assay (H1975 pEGFR IC50 = 0.60 mm) by high-throughput screening of their internal compound library (Figure 3).[23] How-

ever, this compound exhibited high clearance and low oral bioavailability (F = 13 %). Given that the primary metabolites were produced by oxidation of the indazole ring, the authors attempted to optimize this lead compound through addition of substituents to the indazole motif, or replacement of indazole and pyrazole moieties by other heterocycles. However, limited tolerance was observed for morphing the indazole ring. An Xray study rationalized that the N1 nitrogen of indazole was positioned consistent with a hydrogen-bonding interaction with Glu 762. Concurrently, a direct hydrophobic interaction occurred between the indazole phenyl ring and the lipophilic pocket of TMLR. Introduction of electron-withdrawing substituents to this heterocycle was more fruitful. In particular, compound 9 was found to have excellent oral bioavailability (F = ~ 100 %) with high TMLR inhibitory activity (Ki = 34.3 nm). Nonetheless, it possessed only marginal activity in a cell-based assay (H1975 pEGFR IC50 = 3 mm). Another compound (10) not only exhibited high oral bioavailability (F = 62 %) and potent TMLR inhibitory activity (Ki = 9 nm) but also showed acceptable activity in a cell-based assay (H1975 pEGFR IC50 = 0.37 mm). In terms of its binding mode, the pyrazole ring functioned as the hinge-binding element and was involved in the formation of two hydrogen bonds with Gln 791 and Met 793. The indazole N1 nitrogen atom was involved in formation of a hydrogen bond with Glu 762, while the indazole N2 nitrogen atom was situated in a polar environment and may have formed a water-mediated interaction. The dihydrofuropyrimidine moiety was anchored to the center of the active site, with the gem-dimethyl groups occupying the lipophilic ribose pocket and lipophilic contacts between the pyrimidine ring and the side chain of Val 726. Gratifyingly, these two compounds displayed a pan-inhibitor profile that could strongly block both single activated mutations and the T790M double mutants. 2.2. Blockade of FGFRs The FGFR family has four members, FGFR1–4, which can regulate a range of physiological processes, including embryogenesis, tissue repair, and wound healing, by binding to a diverse family of 18 FGF ligands.[24–26] The aberrant FGFR signaling activated by gene amplification, point mutations, or chromosomal translocations is an oncogenic driver in multiple types of malignancies, such as urothelial, breast, and squamous lung cancers.[27] Additionally, the constitutive signaling within this class of kinase is closely correlated with poor prognosis, metastatic

Figure 3. Discovery of indazole derivatives 8–10 as EGFR inhibitors.

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Minireviews progression, and resistance to approved therapies.[28] Owing to the high degree of homology among FGFRs and VEGFRs, the early FGFR inhibitors are predominantly multi-targeted drugs, which increases their chances of side effects or severe toxicity. Therefore, identification of potent and selective FGFRs inhibitors is an unmet medical need, although several FGFR-selective inhibitors have progressed into clinical trials, such as NVPBGJ398, AZD4547, CH5183284, LY2874455, and JNJ42756493.[29–33] A wide range of small molecules bearing an indazole nucleus were documented to have FGFR inhibitory activity. Turner et al. described the use of a de novo-based design approach to identify initial hits and found an indazole-based pharmacophore that showed encouraging levels of inhibition toward FGFRs.[34] Similarly, based on compounds LY2874455 and 11, Yan et al. developed novel 3-benzimidazole-5-pyridylalkoxy-1H-indazole derivatives as potent FGFR inhibitors using a hybridization strategy (Figure 4).[35, 36] The pan-FGFR inhibitor 12 was the most promising one in this chemical series. It strongly and selectively inhibited FGFR1–4, with IC50 values of 0.9, 2.0, 2.0, and 6.1 nm, respectively. Moreover, this compound also showed potent antiproliferative activity against four FGFRdriven cancer cell lines (KG1, NCI-H1581, SNU16, and RT112), with IC50 values below 0.1 nm. And pleasingly, after oral administration of this compound at a dose of 10 mg kg@1 per day for 21 days, tumor growth was completely inhibited in an NCIH1581 (FGFR1-amplified) xenograft mouse model, with tumor growth inhibition (TGI) of 96.9 %, without significant body loss. A docking study revealed the indazole core was tightly anchored to the hinge region of the FGFR1 kinase domain (PDB ID: 3WJ6) by formation of two highly conserved hydrogen bonds with Glu 562 and Ala 564. The (R)-methyl group in the linkage between the pyridine ring and the indazole core fit into a pocket surrounded by Asp 641, Val 492, and Glu 485, thus promoting the pyridine ring to form a strong hydrogen bond

with Asn 568. In contrast, an (S)-methyl group would have an unfavored steric hindrance effect with Val 492. The benzimidazole moiety is fully embedded within a narrow hydrophobic cleft, with the 5’-substituent extending out of this pocket into the solvent-exposed region. This conformation is reinforced by a hydrogen bond between Ala 564 and the benzimidazole moiety. This binding information provided an explanation for the observation that 4’-substitution of benzimidazole was not tolerable, while a range of functional groups was tolerated at the 5’-position. AZD4547, currently in phase II clinical trials, is a highly potent and selective FGFR1–3 inhibitor with low nanomolar potency at the biochemical level.[31] Based on the structure of AZD4547, Liu et al. explored a host of indazole derivatives as FGFR inhibitors using the scaffold hopping strategy (Figure 5).[37] As expected, the indazole ring participated in hydrogen bonding contacts with backbone amides in the hinge region of FGFR1. The N-ethyl-4-phenylpiperazine functionality was demonstrated to be crucial for cellular potency. In this chemotype, compound 13 was confirmed as the most potent FGFR1 inhibitor, with high enzymatic and cellular activities (IC50 = 2.9 and 40.5 nm, respectively). In addition, it also exhibited good potency against FGFR2. Given that fluorine could improve permeability through modulation of molecule lipophilicity, reduction of amine basicity, or direct fluorine–protein interactions,[38] 13 was further refined by incorporation of fluorine into different positions on this skeleton. However, it was found that rings B and C did not tolerate any fluorine substitution patterns, as the activities of these derivatives decreased both in enzymes and cells. Compared with hit 13, compound 14, bearing an additional fluorine on the A ring, exhibited elevated enzymatic and antiproliferative activities. In addition to forming hydrogen bonds with the hinge region, the indazole core interacts with Phe 489 through p–p stacking, due to a change in orientation caused by two fluorine atoms on the A ring. In

Figure 4. Design of indazole derivative 12 as an FGFR inhibitor. Reproduced with permission from Ref. [36]. Copyright American Chemical Society, 2016.

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Figure 5. Design of indazole derivatives 13–16 as FGFR inhibitors.

particular, Zhao et al. described a class of 1H-pyrazolo[3,4b]pyridine derivatives as potent and selective FGFRs inhibitors using the same strategy.[39] Notably, substitution from the 1Hindazole to 1H-pyrazolo[3,4-b]pyridine resulted in a significant increase in enzymatic potency, suggesting that, in some cases, indazole can be used as building block for preparation of more potent compounds. In this study, compound 15 was documented to have many outstanding in vitro and in vivo biological properties. In light of the aforementioned compounds all focusing on optimization at the C3 position of the indazole scaffold, Zhang and co-workers designed a library of novel FGFR inhibitors containing a 6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-indazole fragment with substituent variation at the C4 position of indazole, for the purpose of extending into a new binding subpocket in the ATP site of FGFR.[40] Structure–activity relationship (SAR) analysis indicated that replacement of the phenyl ring (A ring) with other heterocycles, such as pyridine and pyrimidine rings, slightly decreased activity. Substituents at the meta-position of phenyl showed better inhibitory effects than those at other positions. Through several rounds of optimization, compound 16 was characterized as the most appealing FGFR1 inhibitor, with IC50 value of 30.2 nm. 2.3. Inhibition of VEGFRs Angiogenesis is associated not only with physiological conditions, such as embryonic development, pregnancy, and menstruation, but also with several pathologic conditions, including cancer, eye diseases, and inflammatory disorders.[41, 42] Angiogenesis is modulated by a plethora of pro- and anti-angiogenic factors. VEGFRs (VEGFR-1, 2, and 3, especially VEGFR-2) ChemMedChem 2018, 13, 1490 – 1507

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are involved in the angiogenesis pathway. Pazopanib, a drug for the treatment of metastatic renal cell carcinoma and soft tissue sarcoma, is a multi-targeted RTK inhibitor that shows potent inhibitory activity not only against VEGFRs, but also toward platelet-derived growth factor receptor (PDGFR-a and -b), and stem cell factor receptor (c-kit). However, its broad spectrum anti-malignant potency results in many adverse effects, such as hypertension, nausea, anorexia, and liver transaminase elevation.[43, 44] As a consequence, greater attention has been drawn to the derivatization of pazopanib as a VEGFR-2 inhibitor. Of note, the 2H-indazole moiety in this structure projects into the back lipophilic pocket of VEGFR-2 and directly interacts with Lys 868 through p–cation interactions. Jia et al. optimized pazopanib by modification of the terminal aniline moiety with the aim of improving binding to the lipophilic residues of VEGFR-2 (Figure 6).[45] Their study revealed that sulfonamide was an important functionality for enzymatic inhibitory activity; the pyrimidine structure on the sulfonamide moiety contributed to increasing enzymatic inhibitory activity, whereas removal of the methyl group on the 4amino moiety (between indazole and pyrimidine) made no substantial difference to VEGFR-2 inhibitory activity. Notably, two compounds (17 and 18) displayed high activity against VEGFR-2 (IC50 values of 25 and 12 nm, respectively), being more effective than pazopanib (IC50 value of 43 nm). Consistently, in the case of anti-angiogenic activity, these two compounds also showed excellent activity relative to pazopanib. Similarly, in another study published by Qi et al., pazopanib was primarily modified on the terminal benzene skeleton and indazole ring to investigate the electronic and steric effects of substituents on this skeleton (Figure 6).[46] Unfortunately, the authors did not describe any detailed SARs or effects. Com-

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Figure 6. Discovery of indazole derivatives 17–19 as VEGFR inhibitors.

pound 19 was the most active among those synthesized and showed superior activity against VEGFR-2 kinase compared with pazopanib (IC50 values: 12 versus 30 nm, respectively). Encouraged by the observations mentioned above, Elsayed and colleagues carried out research to explore the SARs of pazopanib derivatives against VEGFR-2 more deeply by employing distinct design approaches (Figure 7).[47] Firstly, they replaced the 6-amino-2,3-dimethylindazole moiety with a less bulky 5-aminoindazole scaffold to explore the possibility of formation of additional hydrogen bonds. Simultaneously, the methyl group on the amino nitrogen of the C6 indazole position was removed; thus, the resulting derivative may adopt a U-shaped conformation and avoid extending to the lipophilic back pocket. Additionally, the terminal aniline part was investigated by introducing divergent substituents. For this second design ap-

proach, to examine the impact of conformational restriction on the binding mode and VEGFR-2 inhibition potency, free rotation of the indazole ring was restricted by reversing the orientation of the 5-aminoindazole ring. Lastly, the 5-nitro group of the indazole was replaced by a urea moiety, which is expected to be engaged in a network of hydrogen bonding. In the case of the first series, compound 20, with a sulfonamide on the aniline ring at the C4 position, was the most potent with an IC50 value of 24.5 nm, similar to that of pazopanib. Molecular modeling studies revealed that the 2-aminopyrimidine group is involved in formation of two hydrogen bonds with Cys 919 of the hinge region, while the indazole ring participates in hydrophobic interactions with residues Leu 840, Val 848, Ala 866, and Leu 1035 and hydrogen bonding interactions with Gly 843. The sulfonamide group is also engaged in a hydrogen bond with Asn 923. Compound 21, with methoxy substituents on

Figure 7. Design of indazole derivatives 20–21 as VEGFR inhibitors (green lines represent hydrogen bonds). Reproduced with permission from Ref. [47]. Copyright Royal Society of Chemistry, 2016.

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Minireviews the aniline ring, possessed higher VEGFR-2 inhibition potency (IC50 value of 81 nm) than the compounds incorporating more hydrophobic substituents, such as halogens and alkyl groups. Of note, derivative 21 displayed a strong antiproliferative effect against a broad spectrum of cancer cell lines, being far more potent than compound 20. As anticipated, the 5-aminoindazole ring was found to be highly favorable for VEGFR-2 inhibitory activity. Compared with the first series, nevertheless, compounds 20 and 21 exhibited diminished VEGFR-2 inhibitory potency.

3. Indazole derivative as serine/threonine kinase inhibitors The human serine/threonine kinases (STKs) are a large protein family that contains over 500 members. These kinases are involved in various physiological processes. However, deregulated activation of some of these protein kinases have been connected to tumor initiation and progression. Accordingly, the development of effective inhibitors against certain STKs has been regard as an alternative approach to oncology therapeutics.

3.1. PLK inhibitors The Polo-like kinase (PLK) family has five members, PLK1–5, with PLK1 being the most extensively studied to date. There are several PLK1 inhibitors currently undergoing clinical trials. In contrast, PLK4, the most structurally diverse member of this family, has not, as yet, received much attention. It has been evidenced that overexpression of PLK4 results in loss of centrosome numerical integrity and chromosome instability, a characteristic for evolution of more malignant phenotypes.[48] Pauls’s research group made tremendous efforts to develop PLK4 inhibitor with drug-like properties (Figure 8).[49–51] Beginning with hit 4-hydroxybenzylideneindolin-2-one, obtained from a focused screening approach, authors tried to morph the phenol into bioisosteric heterocycles. The results indicated that the indazole ring (compound A1) held the most promise among these heterocycles for its ability to make hinge region interactions. Interestingly, not hydrogen-bond acceptors/donors, but hydrophobes and halogens were favored at the C5 position. Structure-guided development of compound 22 was of high interest, with desirable PLK4 potency, good selectivity over other members of the PLK family, and potent tumor growth in-

Figure 8. Discovery of indazole derivatives 22–26 as PLK inhibitors. Reproduced with permission from Ref. [51]. Copyright American Chemical Society, 2015.

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Minireviews hibition in MCF-7, MDA-MB-468, and MDA-MB-231 cells as well as a mouse xenograft model (intraperitoneal) IP dosing. Unfortunately, compound 22 exhibited poor PK properties, particularly, low oral exposure. An additional drawback is the configurational lability inherent in this alkene-linked inhibitor. However, the configurational stability and physicochemical properties would be improved through bioisosteric replacement of this double bond with a cyclopropane ring, a frequently occurred group in natural products and pharmaceuticals. In addition, the optimization of the pyridyl group on 22 was undertaken with the view of attenuating inhibitory activities on CYP 2C9 and 2C19 caused by this heterocycle. It is gratifying to see that the cyclopropyl modification not only retained PLK4 affinity and antiproliferative activity but also substantially improved the PK and physicochemical properties. Additionally, compared with alkene-linked compounds, cyclopropane-linked congeners exhibited better aqueous solubility, attributed to the nature of the cyclopropane ring, orthogonal to the plane of the indolinone (decreased planarity). Iterations of structure-based design furnished the most promising compounds, 23 and 24, with excellent activities and PK properties. Of particular note, 24 not only showed substantially raised selectivity over Flt3 and KDR, but it also exhibited excellent drug-like properties, bearing a solubilizing morpholine group. It should be noted that cyclopropane linker compounds have two stereogenic centers, and all of these compounds tested were racemates. The X-ray study suggested that the 1R,2S enantiomer was likely to have preferential affinity over the 1S,2R enantiomer. Inspired by this observation, authors developed a stereoselective synthetic approach to further optimization of this series. As anticipated, the most active stereoisomer of this series was found to be of 1R,2S orientation. Gratifyingly, an orally bioavailable morpholine analogue (25), with excellent in vitro and in vivo activities, was selected for clinical development. In addition, this research group also described “directly linked” modification of hit A1 to develop FLK4 inhibitors with the aim of decreasing molecular weight and logP, which may enhance selectivity profiles and physicochemical properties.[52] In this investigation, the oral bioavailability of compound 26 was found to be 22 %, while the tumor growth inhibition in an MDA-MB-468 xenograft study was up to 96 %. Based on the above results, it seems the vinyl moiety is unnecessary for activity. A model of representative compound 25 in the PLK4 active site (PDB ID: 4JXF) is shown in Figure 8.[51] A hydrogen bonding network in the hinge region is observed between the indazole ring and the backbone carbonyl and the NH of Glu 90 and Cys 92, respectively. Two other hydrogen bonds are formed be-

tween the indolinone and the side chains of Lys 41 and Gln 160. The morpholine is at the protein–water interface. There are extensive hydrophobic contacts between the enzyme and the ligand, especially surrounding the aromatic rings. The methoxy group nestles in a groove bound by the protein backbone and the side chains of Leu 143 and Glu 96. 3.2. Aurora kinase inhibitors Aurora kinases (aurora A, B, and C) are critical regulators of mitosis. Both aurora A and aurora B are highly expressed in various human malignancies, such as breast, ovarian, and thyroid cancers. Using a fragment-based drug discovery (FBDD) strategy, Chang et al. described their efforts in the discovery of indazole derivatives with potent inhibitory activity against aurora kinases (Figure 9).[53] Initially, hit 27 was identified by substructure screening of an in-house library (IC50 value of 13 mm against aurora A). Subsequently, hit-to-lead optimization was undertaken using an in silico FBDD approach, and the acryloyl fragment was found to have the highest Ludi_3_score, which encouraged Chang et al. to synthesize a set of acryloyl analogues. Among these, compound 28, carrying a negatively charged carboxylic group with Z-geometry, showed improved inhibitory activity against aurora A with IC50 value of 0.79 mm. Considering that potency may be improved by addition of a phenyl ring onto the indazole skeleton to increase hydrophobic interactions, various substituents were introduced at the C5 or C6 position of the indazole ring of 28. The results revealed that a hydrophobic preference at the C5 position was a common characteristic of this indazole series, and phenyl sulfonamide derivative 29 was identified as the most potent dual aurora A and B inhibitor, with IC50 values of 0.026 and 0.015 mm, respectively. Electronic properties of the substituent at the 4-position of benzenesulfonamide had little effect on aurora A inhibition, whereas bulky substituents were unfavorable for aurora kinase inhibition. 3.3. CDK inhibitors Members of the cyclin-dependent kinase (CDK) family participate in the regulation of the cell-cycle (CDK1, CDK4, CDK5) or transcription (CDK7, CDK8, CDK9, CDK19 [also known as CDK11], CDK20).[54] In particular, CDK8 has been identified as an oncoprotein that promotes the proliferation of colorectal cancer cells and melanoma cells.[55, 56] Also, it correlates with a worse prognosis in colon, breast, and ovarian cancers.[57, 58] CDK19, as the paralogue of CDK8, has been shown to be specifically overexpressed in the progression of prostate cancer.[59]

Figure 9. Discovery of indazole derivatives 28–29 as aurora kinase inhibitors.

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Figure 10. Identification of indazole derivative 30 as a CDK inhibitor. Reproduced with permission from Ref. [62]. Copyright American Chemical Society, 2016.

This has led to considerable interest in developing drugs that specifically suppress the CDK8 and CDK19 kinases. Beginning with an inhibitor of WNT signaling (CCT251545),[60] an equipotent inhibitor of CDK8 and CDK19,[61] a series of indazole-containing compounds was developed into a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19 (Figure 10).[62] CCT251545 is a high affinity ligand for CDK8 and CDK19; however, it suffers from poor pharmacokinetic properties (including high predicted human clearance, low volumes of distribution, etc.) and aqueous kinetic and thermodynamic solubilities. Optimization of this lead compound resulted in the discovery of compound 30, which exhibited the best compromise between in vitro biochemical activities and pharmacokinetic properties. Structurally, this compound can form three hydrogen bonds with Asp 98, Ala 100, and Lys 52 of CDK8 (PDB ID: 5HBJ). The indazole phenyl ring participates in a cation–p interaction with Arg 365. Notably, the amino functionality at the C2 position could decrease metabolism by diminishing its lipophilicity. Similarly, in other research, Schiemann et al. described the discovery and optimization of 3-benzylindazoles as potent and selective inhibitors of CDK8 and CDK19 from an HSP90 pharmacophore (Figure 11).[57] The 3-benzylindazole skeleton was obtained by high-throughput screening of HSP90 inhibitors. In this study, the authors focused their attention on optimizing this skeleton at the C3 and C5 positions, and many molecules were found to be potent CDK8 inhibitors, with IC50 values in the single-digit nanomolar range. Of note, compound 31, containing two indazole units, proved to be the most promising, with favorable biochemical and cellular potencies (IC50 values for CDK8 and the 7df3 cell line were 10 and 65 nm, respectively), solubility (kinetic solubility > 200 mm), metabolic stability (Clint [human] < 10 mL min@1 mg@1), and efflux ratio.

Figure 11. Identification of indazole derivative 31 as a CDK inhibitor.

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3.4. Inhibition of TTK Tyrosine threonine kinase (TTK), also known as monopolar spindle 1 (Mps1) or phosphotyrosine-picked threonine kinase (PYT), is a key regulator of the spindle assembly checkpoint whose function is to maintain genomic integrity.[63] TTK is overexpressed in a variety of solid cancers, and its expression level correlates with high histological grades in tumors.[64–66] In contrast, reduction of the level of TTK by RNAi in aneuploid cells could decrease the survival rate of cancer cells and induce their apoptosis,[65] suggesting that TTK is a promising target in the development of anticancer therapeutics. Accordingly, discovery of TTK inhibitors has received considerable attention. Interestingly, a striking feature in recently reported inhibitors is the common occurrence of an indazole core, which functions as a critical element for formation of hydrogen bonds with hinge region residues. Taking anthrapyrazolone (SP600125) as a starting point, Kusakabe et al. described their efforts to identify novel indazolebased TTK inhibitors using a structure-based design strategy (Figure 12).[67] Anthrapyrazolone possesses excellent inhibitory activity against Mps1 (IC50 = 98 nm), but its poor selectivity causes wide restrictions on further development. In view of its good lead profile and no specific interactions of its carbonyl group with amino acid residues, authors designed a class of indazoles by truncating the carbonyl group of anthrapyrazolone. A crystal structure study suggested that the phenyl ring and the 5- and 6-positions of the indazole scaffold are critical points for modification. As expected, optimization of the phenyl ring and 6-position of the indazole core led to the discovery of the most potent TTK inhibitor (32) in this series, with an IC50 value of 3.06 nm. Intrigued by the importance of permeability on cellular potency, Kusakabe et al. focused on exploring substituents at the 5-position of the indazole scaffold to increase its lipophilicity. From this effort, amino analogue 33 bearing cyclohexyloxy group emerged as a promising validated lead compound with improved potency for cellular Mps1 and A549 lung cancer cells. However, both compounds were subject to poor oral bioavailability. The crystal structure of this series of compounds bound to TTK showed that the two nitrogen atoms of the indazole ring form two hydrogen bonds with

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Figure 12. Design of indazole derivatives 32–33 as TTK inhibitors. Reproduced with permission from Ref. [67]. Copyright American Chemical Society, 2013.

the hinge backbone carbonyl of Glu 603 and the NH of Gly 605. The sulfonamide NH2 on the phenyl ring also forms two hydrogen bonds with the carbonyls of Gly 605 and Asn 606, respectively. Moreover, four additional hydrogen bonds are formed between the sulfonamide oxygen atoms and the side chains of Lys 529, Gln 541, and Cys 604. This observation explains why the activity was significantly increased when a sulfonamide was introduced at the meta-position of the phenyl ring. Similarly, indazole-based benzenesulfonamides as potent TTK inhibitors were also reported by Laufer et al. In this study, the 3-arylindazole core was obtained through a screening approach (Figure 13).[68] Motivated by the structure of pazopanib, the sulfonamide group was introduced to provide additional interactions with polar functionalities within the active site of TTK or engage in formation of hydrogen bonds. Preliminary studies revealed substituents at the C5 position of the indazole ring are closely related to activity; thus, systematic optimization work focusing exclusively on this position was performed. Separate from the work mentioned above, the aryl terminal groups on the C5 position of the indazole were mediated by a variety of linkers. Consistently, the SAR underscored the importance of the linker in conferring optimal activity, and an amide was found to be an excellent linker here. Eventually, among these compounds, 34 and 35 showed the most potent TTK in-

hibitory activities, coupled with cell growth inhibitory effects. Nevertheless, lack of oral bioavailability prevented them from moving forward, with their detrimental permeability believed to be caused by the polar nature of the sulfonamide group. To discover orally bioavailable TTK inhibitors, while maintaining selectivity and potency, the same research team continued to elaborate these structures by optimizing both phenyl ring substituents and the 5-position of the indazole core.[69] As expected, transformation of the 3-sulfonamide group to a heterocycle at the 4-position of the phenyl ring maintained TTK potency and markedly improved the pharmacokinetic properties. Ten compounds with excellent potency, selectivity, microsomal stability, and cellular activity were selected for in vivo studies. Compounds incorporating the 8-oxa-3-azabicyclo[3.2.1]octan3-yl and 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl bicyclic systems were found to have high exposure upon oral dosing in mice. Indazole derivative 36 was of particular note, with TGI of 77 % in an HCT116 tumor xenograft model at 35 mg kg@1 p.o. 3.5. Inhibition of the Ras/MAPK pathway Aberrant activation of the RAS-RAF-MEK-ERK (MAPK) signaling pathway can be detected in a variety of human cancers, suggesting that blockade of these kinases is another way to ach-

Figure 13. Identification of indazole derivatives 34–36 as TTK inhibitors.

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Minireviews ieve therapeutic benefits. Based on a fragment-based drug discovery strategy, Aman et al. designed a series of 3-carboxamido-2H-indazole-6-arylamide derivatives as potential selective CRAF inhibitors (Figure 14).[70] Among these synthesized compounds, 37 was demonstrated to be a very potent and selective CRAF inhibitor (IC50 value of 38.6 nm) and exhibited greater than 270-fold selectivity over BRAF kinase (9.45 mm). This result was explained by a molecular docking study, which showed that compound 37 bound to the CRAF kinase (PDB ID: 3OMV) through multiple interactions: two hydrogen bonds between two nitrogen atoms of indazole and hinge residue Cys 424, and two more hydrogen bonds to extended hinge residues Trp 423 and Lys 431; an additional hydrogen bond between the middle amide bond and Ser 357; a p–p interaction between indazole and Trp 423; and a p–cation interaction between the imidazole ring and Lys 470. In the case of BRAF V600E (PDB ID: 1UWJ), the hydrogen bond is barely formed in the hinge region and only two hydrogen bonds are formed between the imidazole tail and residues Gly 533 and Ser 601. Additionally, this compound also displayed strong antiproliferative activity against the WM3629 melanoma cell line, with a GI50 value of 0.65 mm. In terms of this signaling pathway, Li et al. developed an array of indazole-containing compounds as ERK1/2 inhibitors from 38, which was identified by screening of their in-house compound collection (Figure 15).[71] A docking model indicated that the indazole nitrogen atoms formed two hydrogen bonds with Asp 104 and Met 106 in the hinge region of ERK2. In this study, two compounds (39 and 40) exhibited both potent enzymatic and cellular activity toward ERK1/2, as well as toward

the HT29 cell line (harboring the BRAF V600E mutation). Unfortunately, their poor pharmacokinetic profiles precluded them from advancing into in vivo studies. As downstream effectors of this pathway, the p90 ribosomal kinases (RSKs) can be phosphorylated by ERK1/2 and thus promote cell migration and invasion. Indazole derivative 41, bearing an a-cyanoacrylamide moiety, was also reported to be a potent and selective RSK2 inhibitor (IC50 values for RSK2 and RSK2 T493M were 12 and < 2.5 nm, respectively) by reversibly and covalently binding to Cys 436 of RSK2.[72] 3.6. Inhibition of Pim kinases The proviral insertion site for moloney murine lymphomia virus (Pim) oncogene family consists of three kinases (Pim-1, Pim-2, and Pim-3), which can promote tumorigenesis and the growth of solid tumors. By means of high-throughput screening, Wang et al. found hit compound 42 to possess single- to doubledigit nanomolar pan Pim kinase potency (Figure 16).[73] Optimization of this compound resulted in the discovery of 43, with sub-nanomolar to nanomolar biochemical potencies for pan Pim kinases. Structurally, the indazole NH group engages in a hydrogen bonding interaction with Glu 121 in the hinge region of Pim-1 (PDB ID: 4WRS), and one nitrogen of the pyrazine ring makes a hydrogen bond to Lys 67. The piperidine places the 3-alkoxy substituent in an axial orientation. It is interesting to note that the spirocyclopropyl group not only appears to favor the axial conformation but also can form van der Waals contacts with the glycine-rich loop (Leu 44 and Gly 45) and the benzene ring of the Phe 49 side chain.

Figure 14. Identification of indazole derivative 37 as a selective CRAF inhibitor. Reproduced with permission from Ref. [70]. Copyright Elsevier, 2016.

Figure 15. Identification of indazole derivative 39–41 as selective CRAF inhibitors or RSK2 inhibitors.

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Figure 16. Identification of indazole derivative 43 as a potent pan-Pim kinase inhibitor. Reproduced with permission from Ref. [73]. Copyright Elsevier, 2015.

4. Inhibition of other kinases (PI3Ks and PDK1) Phosphatidyinsoitol-3-kinases (PI3Ks) consist of 15 proteins that can be separated into four classes. They can regulate the PI3K/AKT/mTOR signaling pathways that are involved in processes linked to survival, growth, proliferation, and metabolism as well as specialized differentiated functions of cells.[74] Deregulated activation of PI3Ks has been connected to tumor initiation, progression, and resistance to antineoplastic drugs.[75] Currently, a variety of the agents developed are being evaluated in early-stage clinical trials[75] For example, GDC-0941(pictilisib), an indazole derivative, has been identified as a potent, selective, orally bioavailable inhibitor of class I PI3Ks.[76] Also, it can enhance the antineoplastic efficacy of anticancer drug axitinib against c-myc-amplified medulloblastoma.[77] This promising result has encouraged the development of PI3K inhibitors. Starting from hit 44 (IC50 value of 900 nm against PI3Ka), Dugar et al. characterized dozens of indazole-substituted morpholino-triazine derivatives as PI3K inhibitors through multistep optimization (Figure 17).[78] Considering that the morpholine is a critical moiety for interacting with the hinge region Val 882 residue of the PI3K protein, their attentions were primarily shifted to the phenolic group and glycine moiety. After a first round of optimization, compound 45 was selected for further improvement based on its potency against PI3Ka (IC50 value of 540 nm). Driven by a generally accepted observation that a phenol moiety would impart poor pharmacokinetic properties to a compound, authors drew their attention to

modifying the phenol moiety. Coincidentally, compound 46, bearing an indazole ring, was found to be the most suitable alternate to phenol with a minimal loss of potency (IC50 value of 1100 nm). Next, efforts for further optimization were centered on substituents on the glycine amide side chain. Among these synthesized derivatives, compounds 47–49 were determined to have the most potent PI3Ka inhibitory activity, with the same IC50 values of 60 nm. Consistently, they also showed strong cellular potency against the human ovarian cell line (A2780), with EC50 values of 520, 680, and 720 nm, respectively. Further studies disclosed that 47 was an orally bioavailable inhibitor and possessed a diverse array of excellent properties, such as metabolic stability, no hERG liability, and tolerability. 3-Phosphoinositide-dependent protein kinase-1 (PDK1), an integral component of the PI3K/AKT/mTOR signaling pathway, plays a central role in phosphorylating and activating the AGC kinase members regulated by PI3Ks.[79] Therefore, PDK1 provides an attractive target for the development of oncologic therapeutics. Through application of fragment-based design strategies, coupled with in silico virtual screening and biochemical kinase assays, Chen et al. discovered (1H-benzo[d]imidazol-2-yl)-1H-indazol derivatives as potent PDK1 inhibitors (Figure 18).[80] After several rounds of optimization, two derivatives (50 and 51) were determined to be lead compounds, with IC50 values of 80 and 90 nm, respectively. More importantly, these two compounds showed a wide spectrum of excellent biological activities, such as potent abilities to inhibit the phosphorylation of AKT and p70S6, selective abilities to kill cancer

Figure 17. Identification of indazole derivatives 46–49 as PI3K inhibitors.

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Figure 18. Identification of indazole derivatives 50–51 as PDK1 inhibitors. Reproduced with permission from Ref. [80]. Copyright Elsevier, 2017.

cells harboring mutations in both PTEN and PI3K, and robust inhibition of tumor growth without influencing body weight growth. Further investigations into the binding mode disclosed the indazole ring of compound 50 involves critical interactions with hinge region residues Ser 160 and Tyr 161 of PDK1 (PDB ID: 1Z5M) through formation of two hydrogen bonds. The fused aryl ring of the indazole moiety is associated with nonbonding interactions with the side chains of Leu 159, Leu 88, and the backbone atoms of Gly 89. The benzoimidazole ring participates in p–p stacking interactions with the aryl ring side chain of Tyr 161. The morpholine group positioned in the solvent binding site is also involved in interactions with Lys 165. Additionally, there are multiple interactions of the 2,2-difluoroN-phenylcy-clopropanecarboxamide part with residues Glu 90, Gly 91, and Lys 111. Independently, in other research published by Brzozowski et al., they also found indazole derivatives that possessed correct geometry to bind PDK1 using a molecular modeling-guided design approach.[81]

5. Multitarget kinase inhibitors It is known that cancer is one of the most complicated families of diseases, with various driver oncogenic genes. For example, NSCLC involves EGFRs, ErbB2, PI3KCA mutations, FGFR mutations, and other amplifications/mutations/rearrangements.[82] Multi-targeted inhibition of cancer-associated kinases is an established strategy to improve the efficacy and clinical outcome of targeted therapies, though it may increase the risk of side effects. Furthermore, this approach can decrease the possibility of developing drug resistance. In a recent study, Zhu et al. reported indazole derivatives as multi-targeted protein kinase inhibitors for the treatment of NSCLC (Figure 19).[83] In this study,

hit compound 52 was obtained by molecular docking-based virtual screening, and further optimization was carried out within the P-loop interaction region, hydrophobic pocket, and hinge interaction region. Replacement of the 3-furan fragment of 52 with a substituted benzene ring resulted in improved FGFR inhibitory activity, which was attributed to the increased hydrophobic shape complementarity within the hydrophobic pocket of FGFRs. As a pivotal hydrogen bond-donating group within the hinge region of FGFR, replacement of the indazole moiety of 52 with other heteroaryl moieties generally led to impaired potency. Furthermore, the chirality (R isomer) and the terminal hydroxy group of 1-hydroxymethyl-1-phenyl-methylamino moiety of 52 were demonstrated to be essential for maintaining activity. Several rounds of optimization and evaluation gave 53 as the most active compound in this chemotype. It not only strongly inhibited NSCLC-related oncogene kinases but also exhibited outstanding antitumor activity in NCI-H1581 NSCLC xenografts (TGI = 66.1 %) with a good pharmacokinetic profile.

6. Regulation of transcription factors (HIF-1 and ER-a) Hypoxia inducible factor-1 (HIF-1), a heterodimeric basic helixloop-helix transcription factor, is highly expressed in various human cancers. It can induce a number of cellular responses such as anaerobic glycolysis, angiogenesis, cell proliferation, and tumor invasion through binding to hypoxic response elements of target genes, including glucose transporter 1 (Glut1), carboanhydrase IX (CAIX), vascular endothelial growth factor (VEGF), and erythropoietin (EPO).[84, 85] In addition, the level of HIF-1 is strongly associated with aggressive tumor growth,

Figure 19. Identification of indazole derivative 53 as a multi-target kinase inhibitor.

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Minireviews therapeutic resistance, and poor patient prognosis.[84] Therefore, it provides an attractive target for the treatment of tumor hypoxia. YC-1, an indazole-furan derivative, is a widely used HIF-1 inhibitor in both in vitro and in vivo experimental investigations.[86] Taking YC-1 as a lead, Sheng et al. found bioisostere analogue compound 54, with HIF-1 inhibitory activity similar to that of YC-1 (Figure 20).[85] With the aim of identifying more potent HIF-1 inhibitors, the same research group continued a comprehensive SAR study of 54 and its derivatives.[85] Modification of the hydroxyethyl moiety of 1,2,4-oxadiazole suggested that aryl substituents are favorable in this position, especially a 4-CF3O-phenyl group. Replacement of the indazole with other aromatic heterocyclic moieties dramatically attenuated HIF-1 inhibition, confirming that the indazole is essential to retain HIF-1 inhibitory activity. Additionally, the influence of indazole tautomerism on HIF-1 inhibitory activity was also investigated, and substituents at the N1 position proved to be more favorable than those at the N2 position. Interestingly, the chlorobenzyl at the N1 position of 54 was a well-tolerated group, because it could be replaced by various aryl substituents without clearly affecting HIF-1 inhibitory potency. Finally, among these designed compounds, the most potent HIF-1 inhibitors, 55 and 56, were 6- to 7-fold more effective than YC-1, with IC50 values of 0.62 and 0.55 mm, respectively. Furthermore, it could remarkably block the hypoxia-driven migration of SKOV3 cells in vitro and tumor metastasis in vivo. Estrogen receptor alpha (ER-a) is a ligand-regulated transcription factor that mediates the activity of estrogens in many important physiological processes, such as reproduction and bone density.[87] Pathologically, it plays a central role in the initiation and progression of breast cancer. Tamoxifen is one of the most commonly used selective ER antagonists for the treatment of ER-positive breast cancer. Unfortunately, numerous patients will develop drug resistance. Evidence showed that ER-a36 is one of the mechanisms for inducing acquired resistance to tamoxifen.[88] Although these resistant cells are sensitive to the approved drug fulvestrant and compound GW5638, the latter was discontinued in clinical trials for unknown reasons, and the former is limited by poor pharmaceutical properties and requires administration by intramuscular injections.[89] This encouraged Lai and colleagues to identify an

orally bioavailable selective estrogen receptor degrader (SERD) with potent ER-a degrading properties.[89] Optimization work was carried out by modifying the three benzene rings (designated R1, R2, and R3) on the skeleton of GW-5638 (Figure 21). SAR studies indicated that bicyclic heterocycles were favorable for R1; however, they were not well tolerated on the R2 ring. Replacement of R1 with a 5-indazole ring led to a significant increase in activity. The 4-indazole ring maintained potency compared to the 5-indazole ring, while the 6-indazole isomer caused a great decrease in potency. When the optimal groups were placed in the R1 and R2 rings (5-indazole ring and cinnamic acid, respectively), modification of the R3 ring led to discovery of a library of SERDs with EC50 values below 1 nm. In particular, apart from high efficacy degraders of the ER-a, compound 57 exhibited good bioavailability and robust activity in tamoxifen-sensitive and tamoxifen-resistant xenograft models of breast cancer. Currently, this compound is in clinical trials. Subsequently, the same group continued to explore the SARs of 57 by incorporating varying substituents on R1, R3, and R4.[90] Slight potency enhancement was realized by introducing a linear CN group to the 4-position of indazole ring; however, it was accompanied by a dramatic loss of oral bioavailability. In contrast, a 3-fluoro analogue showed a slight improvement in oral bioavailability. Ultimately, their efforts culminated in the identification of indazoles 58 and 59, with great potential in inducing tumor regression in a tamoxifen-resistant breast cancer xenograft.

7. Ligands of metal-based anticancer agents As we all know, approximately 50 % of cancers can be routinely treated with platinum-based drugs, such as cisplatin and oxaliplatin. Their demonstrable success has stimulated the development of new metal-based anti-cancer analogues. Recently, incorporation of a heterocyclic moiety as a ligand for metals has received much attention. Among these heterocyclic rings, indazole is of particular interest. Two prominent examples of these organometallic compounds are KP1019 and NKP1339, which are in clinical trials as potential anticancer agents.[91] On one hand, indazole can maintain the square-planar geometry of the complexes, which is necessary for forming the DNA lesions. On the other hand, the anticancer effect could be enhanced

Figure 20. Identification of indazole derivatives 54–56 as HIF-1 inhibitors.

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Minireviews lines CH1, SW480, and A549 but inferior in a Hep3B SCID mouse xenotransplantation model.[98] It is worth noting that substituents on the indazole framework also clearly affected their activities. In studies of KP1019 and NKP-1339 derivatives, Chang et al. found that the cytotoxicity of these complexes was significantly enhanced when CF3 groups were added to the indazole moiety, suggesting greater lipophilicity may enhance passive diffusion of the complexes through cell membranes, resulting in greater intracellular concentrations and enhanced activity.[93]

8. Summary and outlook Intrinsic or acquired drug resistance is still the main barrier to attaining effective results with chemotherapy.[99, 100] Therefore, discovery of new anticancer drugs or chemoreversal agents to treat cancers is needed. Fragment-based drug discovery is an effi-

Figure 21. Identification of indazole derivatives 57–59 as ER antagonists.

by complementary p–p stacking and dipole–dipole interactions between indazole fragments of the ligand and the nitrogenated bases. Apart from the well-studied indazole-ruthenium(III) complexes,[92–94] Cabrera et al. quite recently presented six new imidoyl-indazole platinum(II) complexes as potential anticancer agents.[95] In their study, both ammonia ligands in cisplatin were substituted by an N,N-imidoyl-indazole system, which served as a bidentate ligand, in which one of the N-donors in this ligand belonged to the indazole moiety and the other Ndonor arises from a Schiff base. Results suggested that all of the complexes showed higher cytotoxicity and selectivity than their respective ligands alone or cisplatin in the tested cancer cell lines. This enhanced antitumor effect may be ascribed to increased passive uptake, as well as stability. A further cell death mechanism study revealed these complexes could induce tumor cell necroptosis, instead of apoptosis. Cytotoxic PtIIbased complexes 60 and 61 were found to be the most promising ones in this work (Figure 22). Additionally, indazole osmium analogues with anticancer activity were also reported.[96] In the research performed by Bechel et al., osmium(IV) complex 62 and its one-electron-reduced species 63 (osmium(III)) were found to have strong antiproliferative effects on tested cancer cells at concentrations between 30 and 300 mm (Figure 22). Specially, these two osmium complexes showed a higher antiproliferative activity toward the HT29 cell line than that of cisplatin. Of particular note, indazole was coordinated to transition metals predominantly through N2 (1H-indazole), whereas in osmium complexes, it was bound either by an N2 (1H-indazole) or N1 atom (2H-indazole).[97] However, different binding modes significantly affected their biological properties. For example, investigations on the antiproliferative activity of [OsIVCl5(Hind)]@ , where Hind is 1H- or 2H-indazole, showed that the 2H-tautomer is superior in the three human cancer cell ChemMedChem 2018, 13, 1490 – 1507

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Figure 22. Discovery of metal-based indazole derivatives 60–63 as anticancer agents.

cient methodology in designing drug-like molecules, and indazole is a privileged scaffold that widely occurs in many biological molecules and pharmaceutical products. It is evident from the above discussion that indazole derivatives possess immense potential as anticancer agents. Interestingly, most of these indazole analogues were initially identified through screening approaches or scaffold hopping strategies. Indazolebased derivatives have attracted tremendous continued attention and long-lasting interest. The current study focused on the anticancer activities of recently developed indazole derivatives on various targets, and analysis of their structural features showed that: (1) 1H-indazole is the most extensively studied

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Minireviews tautomeric form. N1 and N2 are conserved positions in most studies, underlining the biological importance of the hydrogen bond acceptor and donor properties of indazolyl nitrogen atoms. The pyrazole ring of the indazole skeleton can be involved in formation of hydrogen bonds as a hydrogen bond acceptor and/or donor with amino acid residues of the hinge region, which contributes significantly to enzyme inhibition. The phenyl moiety of the indazole furnishes favorable hydrophobic gatekeeper interactions. The C3 and C5 positions appear to be crucial for modification and, in most cases, aromatic rings are attached to these positions directly or by a linker, such as an amide, double bond, or amine. (2) 2-Substituted-2H-indazole is also a promising scaffold in medicinal chemistry, with some therapeutic agents like pazopanib and niraparib containing this core. p–Cation and p–p interactions can be formed between the indazole core and certain amino acid residues (Lys, Arg, Trp, etc.). (3) Indazole provides a permanent coordination site for metals. The p–p stacking and dipole–dipole interactions between indazole fragments and the nitrogenated bases could enhance anticancer effects. (4) Introducing nitrogen atom(s) on the indazole motif (azaindole) provides another approach to optimization, as the reduced clogP values may improve potency. (5) Indazole motif could improve pharmacokinetic properties.[101] (6) Alkaline fragments such as piperazine, piperidine, morpholine, and aliphatic amine are widely found in indazole-containing analogues, which are attributed to improving solubility and activity. In general, fine-tuning the substituents on the indazole backbone may afford novel molecules with enhanced anticancer potency, as well as drug-like properties.

Acknowledgements This program was supported financially by the Hong Kong Scholar Program (Grant XJ2015032), the National Natural Science Foundation of China (Grant 21602132), the Shanghai Science and Technology Innovation Program (Grant 15431900700), and the Shanghai Natural Science Fund (Grant 16ZR1418100). J.D. gratefully acknowledges assistance and encouragement from Haixia Zhang.

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