Rational Design and Binding Mode Duality of MDM2鈥損53 Inhibitors
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- 作者：Felix Gonzalez-Lopez de Turiso ; Daqing Sun ; Yosup Rew ; Michael D. Bartberger ; Hilary P. Beck ; Jude Canon ; Ada Chen ; David Chow ; Tiffany L. Correll ; Xin Huang ; Lisa D. Julian ; Frank Kayser ; Mei-Chu Lo ; Alexander M. Long ; Dustin McMinn ; Jonathan D. Oliner ; Tao Osgood ; Jay P. Powers ; Anne Y. Saiki ; Steve Schneider ; Paul Shaffer ; Shou-Hua Xiao ; Peter Yakowec ; Xuelei Yan ; Qiuping Ye ; Dongyin Yu ; Xiaoning Zhao ; Jing Zhou ; Julio C. Medina ; Steven H. Olson
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：May 23, 2013
- 年：2013
- 卷：56
- 期：10
- 页码：4053-4070
- 全文大小：921K
- 年卷期：v.56,no.10(May 23, 2013)
- ISSN：1520-4804
文摘
Structural analysis of both the MDM2鈥損53 protein鈥損rotein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 渭M. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 渭M) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21WAF1 mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.