Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6.
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.
Toogood
Peter L
PL
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
Harvey
Patricia J
PJ
Repine
Joseph T
JT
Sheehan
Derek J
DJ
VanderWel
Scott N
SN
Zhou
Hairong
H
Keller
Paul R
PR
McNamara
Dennis J
DJ
Sherry
Debra
D
Zhu
Tong
T
Brodfuehrer
Joanne
J
Choi
Chung
C
Barvian
Mark R
MR
Fry
David W
DW
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism
D000970:Antineoplastic Agents; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D011743:Pyrimidines; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C495903:Cdk4 protein, rat; C495913:Cdk6 protein, rat; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; C500026:palbociclib; D013936:Thymidine