title: Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases.
abstract: Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that act as key regulatory elements in cell cycle progression. We describe the development of highly potent diaminothiazole inhibitors of CDK2 (IC50 = 0.0009-0.0015 μM) from a single hit compound with weak inhibitory activity (IC50 = 15 μM), discovered by high-throughput screening. Structure-based design was performed using 35 cocrystal structures of CDK2 liganded with distinct analogues of the parent compound. The profiling of compound 51 against a panel of 339 kinases revealed high selectivity for CDKs, with preference for CDK2 and CDK5 over CDK9, CDK1, CDK4, and CDK6. Compound 51 inhibited the proliferation of 13 out of 15 cancer cell lines with IC50 values between 0.27 and 6.9 μM, which correlated with the complete suppression of retinoblastoma phosphorylation and the onset of apoptosis. Combined, the results demonstrate the potential of this new inhibitors series for further development into CDK-specific chemical probes or therapeutics.
authors.affiliation: Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA. ernst.schonbrunn@moffitt.org
authors.forename: Ernst
authors.initials: E
authors.lastname: Schonbrunn
authors.forename: Stephane
authors.initials: S
authors.lastname: Betzi
authors.forename: Riazul
authors.initials: R
authors.lastname: Alam
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Martin
authors.forename: Andreas
authors.initials: A
authors.lastname: Becker
authors.forename: Huijong
authors.initials: H
authors.lastname: Han
authors.forename: Rawle
authors.initials: R
authors.lastname: Francis
authors.forename: Ramappa
authors.initials: R
authors.lastname: Chakrasali
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Jakkaraj
authors.forename: Aslamuzzaman
authors.initials: A
authors.lastname: Kazi
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cubitt
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Gebhard
authors.forename: Lori A
authors.initials: LA
authors.lastname: Hazlehurst
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Tash
authors.forename: Gunda I
authors.initials: GI
authors.lastname: Georg
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D003198:Computer Simulation; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D057166:High-Throughput Screening Assays; D006801:Humans; D007202:Indicators and Reagents; D008297:Male; D008958:Models, Molecular; D010766:Phosphorylation; D013329:Structure-Activity Relationship; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000473:pathology; D013778:Tetrazolium Salts; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D004396:Coloring Agents; D007202:Indicators and Reagents; D013778:Tetrazolium Salts; D013844:Thiazoles; D000071679:Glycogen Synthase Kinase 3 beta; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; D020169:Caspases; C022616:thiazolyl blue