Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2: synthesis, X-ray crystallographic analysis, and biological activities.
High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC(50) values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase alpha (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2.
Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. kyoung.kim@bms.com
Kyoung Soon
KS
Kim
S David
SD
Kimball
Raj N
RN
Misra
David B
DB
Rawlins
John T
JT
Hunt
Hai-Yun
HY
Xiao
Songfeng
S
Lu
Ligang
L
Qian
Wen-Ching
WC
Han
Weifang
W
Shan
Toomas
T
Mitt
Zhen-Wei
ZW
Cai
Michael A
MA
Poss
Hong
H
Zhu
John S
JS
Sack
John S
JS
Tokarski
Chieh Ying
CY
Chang
Nikola
N
Pavletich
Amrita
A
Kamath
William G
WG
Humphreys
Punit
P
Marathe
Isia
I
Bursuker
Kristen A
KA
Kellar
Urvashi
U
Roongta
Roberta
R
Batorsky
Janet G
JG
Mulheron
David
D
Bol
Craig R
CR
Fairchild
Francis Y
FY
Lee
Kevin R
KR
Webster
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D044482:Benzeneacetamides; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004256:DNA Polymerase I / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D044482:Benzeneacetamides; D019927:Cyclin E; D004791:Enzyme Inhibitors; D006657:Histones; C465460:N-(5-(((5-tert-butyl-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-(((bis(hydroxymethyl)methyl)amino)methyl)benzeneacetamide; D010080:Oxazoles; D016160:Retinoblastoma Protein; D013844:Thiazoles; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D004256:DNA Polymerase I