Discovery of Aminothiazole Inhibitors of Cyclin-Dependent Kinase 2:  Synthesis, X-ray Crystallographic Analysis, and Biological Activities

Kyoung Soon Kim,*† S. David Kimball,‡ Raj N. Misra,† David B. Rawlins,† John T. Hunt,§ Hai-Yun Xiao,† Songfeng Lu,† Ligang Qian,† Wen-Ching Han,† Weifang Shan,† Toomas Mitt,† Zhen-Wei Cai, Michael A. Poss, Hong Zhu, John S. Sack, John S. Tokarski, Chieh Ying Chang, Nikola Pavletich,# Amrita Kamath, William G. Humphreys, Punit Marathe, Isia Bursuker, Kristen A. Kellar,§ Urvashi Roongta,§ Roberta Batorsky,§ Janet G. Mulheron,§ David Bol,§ Craig R. Fairchild,§ Francis Y. Lee,§ and Kevin R. Webster
Departments of Oncology Chemistry, Oncology Drug Discovery, New Leads Chemistry, Structural Biology and Modeling, Metabolism and Pharmacokinetics, and High Throughput Screening, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000
J. Med. Chem., 2002, 45 (18), pp 3905–3927
DOI: 10.1021/jm0201520
Publication Date (Web): August 2, 2002
Copyright © 2002 American Chemical Society
*

 To whom correspondence should be addressed. Tel:  (609)252-5181. Fax:  (609)252-6601. E-mail:  kyoung.kim@bms.com.

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†

 Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute.

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‡

 Lexicon Pharmaceuticals, East Windsor, NJ.

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§

 Department of Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute.

,

 Department of New Leads Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute.

,

 Department of Structural Biology and Modeling, Bristol-Myers Squibb Pharmaceutical Research Institute.

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#

 Memorial Sloan-Kettering Cancer Center, New York, NY.

,

 Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute.

,

 Astra Zeneca R&D Boston Inc., Waltham, MA.

Abstract

Abstract Image

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 IC50 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 α (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.

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History

  • Published In Issue August 29, 2002
  • Received April 9, 2002

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