2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.
Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.
Wang
Shudong
S
Cyclacel Limited, James Lindsay Place, Dundee DD1 5JJ, Scotland, UK.
Meades
Christopher
C
Wood
Gavin
G
Osnowski
Andrew
A
Anderson
Sian
S
Yuill
Rhoda
R
Thomas
Mark
M
Mezna
Mokdad
M
Jackson
Wayne
W
Midgley
Carol
C
Griffiths
Gary
G
Fleming
Ian
I
Green
Simon
S
McNae
Iain
I
Wu
Su-Ying
SY
McInnes
Campbell
C
Zheleva
Daniella
D
Walkinshaw
Malcolm D
MD
Fischer
Peter M
PM
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011743:Pyrimidines; D013844:Thiazoles; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9