CDK2/cyclinA inhibitors: targeting the cyclinA recruitment site with small molecules derived from peptide leads.
The syntheses of potent small molecule inhibitors of the CDK2/cyclinA recruitment site are described. Structure-activity trends of nanomolar octapeptides were examined through amino-acid substitution and truncation of the sequence resulting in the identification of a smaller, albeit significantly less potent, tetrapeptide lead. These losses in affinity were recovered by side-chain optimization and by rigidification of the peptide backbone using a combination of solid-phase parallel synthesis and structure-based design. Finally, two guanidine functionalities were replaced to improve drug-like properties, resulting in neutral small molecules equal in activity to that of the peptide lead.
Castanedo
Georgette
G
Department of Medicinal Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Clark
Kevin
K
Wang
Shumei
S
Tsui
Vickie
V
Wong
Mengling
M
Nicholas
John
J
Wickramasinghe
Dineli
D
Marsters
James C
JC
Sutherlin
Daniel
D
D019943:Amino Acid Substitution; D019925:Cyclin A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019791:Guanidine / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation
D019925:Cyclin A; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D051357:Cyclin-Dependent Kinase 2; D019791:Guanidine