title: Discovery of novel indirubin-3'-monoxime derivatives as potent inhibitors against CDK2 and CDK9.
abstract: Indirubin-3'-monoxime (IM) is a potent cyclin-dependent kinase (CDK) inhibitor. Twenty novel IM derivatives were prepared to investigate the structure-activity relationships (SAR) of this compound class. Six compounds showed significant inhibition against both CDK2/cyclin E1 and CDK9/cyclin T1. The most potent compound 7t exhibited IC50 values at submicromolar level. Preliminary SAR trends were suggested and cytotoxicity of these compounds was investigated. Molecular docking studies on compounds 7l and 7t provided conducive clues for further structural optimization.
authors.affiliation: Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yan
authors.affiliation: Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Lai
authors.affiliation: Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: xiaoz@imm.ac.cn.
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Xiao
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000009:adverse effects*; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D010091:Oximes / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D010091:Oximes; C474021:indirubin-3'-monoxime; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9
keywords: Cyclin-dependent kinase 2; Cyclin-dependent kinase 9; Indirubin-3′-oxime derivatives; Structure–activity relationship