Highly Potent, Selective, and Orally Bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation.
Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell cycle and are validated targets for anticancer drug discovery. Herein we detail the discovery of a novel series of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in 83, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of 83 caused marked inhibition of tumor growth in MV4-11 acute myeloid leukemia mouse xenografts without having a negative effect on body weight and showing any sign of clinical toxicity. The data merit 83 as a clinical development candidate.
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Solomon
0000-0002-9966-2236
S
Tadesse
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Mingfeng
M
Yu
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Laychiluh B
0000-0001-7108-5345
LB
Mekonnen
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Frankie
F
Lam
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Saiful
S
Islam
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Khamis
K
Tomusange
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Muhammed H
MH
Rahaman
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Benjamin
B
Noll
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Sunita K C
SK
Basnet
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Theodosia
T
Teo
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Hugo
0000-0002-3951-1866
H
Albrecht
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Robert
R
Milne
Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
Shudong
0000-0001-6225-5525
S
Wang
D000284:Administration, Oral; D001682:Biological Availability; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases