151. Design, synthesis, and evaluation of 2-methyl- and 2-amino-N-aryl-4,5- dihydrothiazolo[4,5-h]quinazolin-8-amines as ring-constrained 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin-dependent kinase inhibitors
- Author
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Nicholas J. Westwood, Mark P. Thomas, Daniella Zheleva, Wayne Jackson, Alexandra M. Z. Slawin, Anna Barnett, Shudong Wang, David Blake, Peter Fischer, Campbell McInnes, Neil Mcintyre, George Kontopidis, Gary Griffiths, McIntyre, Neil A, McInnes, Campbell, Griffiths, Gary, Barnett, Anna L, Kontopidis, George, Slawin, Alexandra MZ, Jackson, Wayne, Thomas, Mark, Zheleva, Daniella I, Wang, Shudong, Blake, David G, Westwood, Nicholas J, and Fischer, Peter M
- Subjects
Models, Molecular ,crystal structure ,Magnetic Resonance Spectroscopy ,Pyrimidine ,Stereochemistry ,cyclin dependent kinase inhibitors ,CDK ,Blotting, Western ,pyrimidine derivative ,Antineoplastic Agents ,Crystallography, X-Ray ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Cyclin-dependent kinase ,Cell Line, Tumor ,Drug Discovery ,Structure–activity relationship ,Humans ,Protein Kinase Inhibitors ,Cell Proliferation ,biology ,Aryl ,Cyclin-dependent kinase 2 ,Rational design ,Cyclin-Dependent Kinases ,Thiazoles ,chemistry ,Nitro ,Cyclin-dependent kinase complex ,biology.protein ,Aminoquinolines ,Molecular Medicine - Abstract
Following the recent discovery and development of 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin dependent kinase (CDK) inhibitors, a program was initiated to evaluate related ring-constrained analogues, specifically, 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines for inhibition of CDKs. Here we report the rational design, synthesis, structure-activity relationships (SARs), and cellular mode-of-action profile of these second generation CDK inhibitors. Many of the analogues from this chemical series inhibit CDKs with very low nanomolar K(i) values. The most potent compound reported in this study inhibits CDK2 with an IC(50) of 0.7 nM ([ATP] = 100 microM). Furthermore, an X-ray crystal structure of 2-methyl-N-(3-(nitro)phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amine (11g), a representative from the chemical series in complex with cyclin A-CDK2, is reported, confirming the design rationale and expected binding mode within the CDK2 ATP binding pocket. Refereed/Peer-reviewed
- Published
- 2010