Discovery of novel inhibitors of Aurora kinases with indazole scaffold: In silico fragment-based and knowledge-based drug design

• Published in: European journal of medicinal chemistry Vol. 124; pp. 186 - 199
• Main Authors: Chang, Chun-Feng, Lin, Wen-Hsing, Ke, Yi-Yu, Lin, Yih-Shyan, Wang, Wen-Chieh, Chen, Chun-Hwa, Kuo, Po-Chu, Hsu, John T.A., Uang, Biing-Jiun, Hsieh, Hsing-Pang
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 29.11.2016; Elsevier
• Subjects: Aurora Kinase A - antagonists & inhibitors; Aurora Kinase A - chemistry; Aurora kinases inhibitor; Cell Proliferation - drug effects; Chemistry, Medicinal; Computer Simulation; Drug Design; HCT116 Cells; Humans; Indazole; Indazoles - chemistry; Indazoles - pharmacology; Isoform selectivity; Life Sciences & Biomedicine; Ligand efficiency; Molecular Docking Simulation; Pharmacology & Pharmacy; Protein Conformation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Science & Technology; Structure-activity relationship (SAR); Isoform selectivity; Ligand efficiency; Structure-activity relationship (SAR); Aurora kinases inhibitor; Indazole; VIVO; IDENTIFICATION; CANCER; POTENT; GROWTH; SELECTIVE INHIBITORS; OPTIMIZATION; AGENTS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.08.026

Aurora kinases have emerged as important anticancer targets so that there are several inhibitors have advanced into clinical study. Herein, we identified novel indazole derivatives as potent Aurora kinases inhibitors by utilizing in silico fragment-based approach and knowledge-based drug design. After intensive hit-to-lead optimization, compounds 17 (dual Aurora A and B), 21 (Aurora B selective) and 30 (Aurora A selective) possessed indazole privileged scaffold with different substituents, which provide sub-type kinase selectivity. Computational modeling helps in understanding that the isoform selectivity could be targeted specific residue in the Aurora kinase binding pocket in particular targeting residues Arg220, Thr217 or Glu177. New series of indazole-based derivatives were synthesized and structure-activity relationship was constructed. Hit compound from sub-structure search, followed by in silico fragment-based drug design and knowledge-based drug design to discover compound 17 as a potent novel Aurora kinases inhibitor. [Display omitted] •Sub-structure search for hit identification is described.•In silico fragment screening was utilized to rapidly search suitable fragments.•LE and FQ were calculated to assess the fragments.•Compound 17 showed an IC50 value of 26 nM against Aurora kinase A.•Docking study was performed and sub-type selectivity was also discussed.