Triazolo[1,5- a]pyrimidines as novel CDK2 inhibitors: Protein structure-guided design and SAR

• Published in: Bioorganic & medicinal chemistry letters 2006-03, Vol.16 (5), p.1353-1357
• Main Authors: Richardson, Christine M., Williamson, Douglas S., Parratt, Martin J., Borgognoni, Jenifer, Cansfield, Andrew D., Dokurno, Pawel, Francis, Geraint L., Howes, Rob, Moore, Jonathan D., Murray, James B., Robertson, Alan, Surgenor, Allan E., Torrance, Christopher J.
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; CDK2; Cell Line, Tumor; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - metabolism; Drug Design; General aspects; Humans; Inhibitory Concentration 50; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Potency; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; SAR; Selectivity; Structure-Activity Relationship; Structure-guided drug design; Triazoles - chemistry; Triazolo [1,5- a]pyrimidines
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.11.048

Crystallographic and modelling data, in conjunction with a medicinal chemistry template-hopping approach, led to the identification of a series of novel and potent inhibitors of human cyclin-dependent kinase 2 (CDK2), with selectivity over glycogen synthase kinase-3β (GSK-3β). One example had a CDK2 IC 50 of 120 nM and showed selectivity over GSK-3β of 167-fold. Crystallographic and modelling data, in conjunction with a medicinal chemistry template-hopping approach, led to the identification of a series of novel and potent inhibitors of human cyclin-dependent kinase 2 (CDK2), with selectivity over glycogen synthase kinase-3β (GSK-3β). One example had a CDK2 IC 50 of 120 nM and showed selectivity over GSK-3β of 167-fold.