Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6

Peter L Toogood; Patricia J Harvey; Joseph T Repine; Derek J Sheehan; Scott N VanderWel; Hairong Zhou; Paul R Keller; Dennis J McNamara; Debra Sherry; Tong Zhu; Joanne Brodfuehrer; Chung Choi; Mark R Barvian; David W Fry

doi:10.1021/jm049354h

Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6

J Med Chem. 2005 Apr 7;48(7):2388-406. doi: 10.1021/jm049354h.

Authors

Peter L Toogood¹, Patricia J Harvey, Joseph T Repine, Derek J Sheehan, Scott N VanderWel, Hairong Zhou, Paul R Keller, Dennis J McNamara, Debra Sherry, Tong Zhu, Joanne Brodfuehrer, Chung Choi, Mark R Barvian, David W Fry

Affiliation

¹ Medicinal Chemistry, Cancer Pharmacology, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. Peter.toogood2@pfizer.com

PMID: 15801831
DOI: 10.1021/jm049354h

Abstract

A pharmacological approach to inhibition of cyclin-dependent kinases 4 and 6 (Cdk4/6) using highly selective small molecule inhibitors has the potential to provide novel cancer therapies for clinical use. Achieving high levels of selectivity for Cdk4/6, versus other ATP-dependent kinases, presents a significant challenge. The pyrido[2,3-d]pyrimidin-7-one template provides an effective platform for the inhibition of a broad cross-section of kinases, including Cdks. It is now demonstrated that the modification of pyrido[2,3-d]pyrimidin-7-ones to include a 2-aminopyridine side chain at the C2-position provides inhibitors with exquisite selectivity for Cdk4/6 in vitro. This selectivity profile is recapitulated in cells where the most selective inhibitors create a G(1) block at concentrations up to 100-fold the IC(50) for cell proliferation. On the basis of its selectivity profile and pharmacokinetic profile, compound 43 (PD 0332991) was identified as a drug candidate for the treatment of cancer.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Biological Availability
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinases / antagonists & inhibitors*
G1 Phase / drug effects
Humans
Male
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperazines / pharmacology
Proto-Oncogene Proteins / antagonists & inhibitors*
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Thymidine / metabolism

Substances

Antineoplastic Agents
Piperazines
Proto-Oncogene Proteins
Pyridines
Pyrimidines
CDK4 protein, human
CDK6 protein, human
Cdk4 protein, rat
Cdk6 protein, rat
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinases
palbociclib
Thymidine