A novel class of cyclin-dependent kinase inhibitors identified by molecular docking act through a unique mechanism.
The cyclin-dependent kinase (Cdk) family is emerging as an important therapeutic target in the treatment of cancer. Cdks 1, 2, 4, and 6 are the key members that regulate the cell cycle, as opposed to Cdks that control processes such as transcription (Cdk7 and Cdk9). For this reason, Cdks 1, 2, 4, and 6 have been the subject of extensive cell cycle-related research, and consequently many inhibitors have been developed to target these proteins. However, the compounds that comprise the current list of Cdk inhibitors are largely ATP-competitive. Here we report the identification of a novel structural site on Cdk2, which is well conserved between the cell cycle Cdks. Small molecules identified by a high throughput in silico screen of this pocket exhibit cytostatic effects and act by reducing the apparent protein levels of cell cycle Cdks. Drug-induced cell cycle arrest is associated with decreased Rb phosphorylation and decreased expression of E2F-dependent genes. Multiple lines of evidence indicate that the primary mechanism of action of these compounds is the direct induction of Cdk1, Cdk2, and Cdk4 protein aggregation.
Corsino
Patrick
P
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Fliorida 32610-3633, USA.
Horenstein
Nicole
N
Ostrov
David
D
Rowe
Thomas
T
Law
Mary
M
Barrett
Amanda
A
Aslanidi
George
G
Cress
W Douglas
WD
Law
Brian
B
D000255:Adenosine Triphosphate / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050684:E2F Transcription Factors / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism
D050684:E2F Transcription Factors; D047428:Protein Kinase Inhibitors; D016160:Retinoblastoma Protein; D000255:Adenosine Triphosphate; D018844:Cyclin-Dependent Kinases