Selective and Potent Morpholinone Inhibitors of the MDM2–p53 Protein–Protein Interaction
| Autor: | Ada Chen, Steven H. Olson, Alexander M. Long, John Eksterowicz, Michael D. Bartberger, Jing Zhou, Yosup Rew, Lawrence R. McGee, Mei-Chu Lo, Anne Y. Saiki, Dongyin Yu, Jason Duquette, Xuelei Yan, Ana Z. Gonzalez, Hilary Plake Beck, Jonathan B. Houze, Yun Ling, Mcintosh Joel, Jonathan D. Oliner, Sarah Wortman, Jude Canon, Daqing Sun, Dustin McMinn, Brian M. Fox, Paul L. Shaffer, Xiaoning Zhao, Tao Osgood, Lixia Jin, Xin Huang, Zhihong Li, David Chow, Qiuping Ye, Yihong Li, Jiasheng Fu, Peter Yakowec, Julio C. Medina |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Stereochemistry Morpholines Molecular Conformation Antineoplastic Agents Acetates Crystallography X-Ray Protein–protein interaction Mice Structure-Activity Relationship Cell Line Tumor Drug Discovery Animals Humans Potency Structure–activity relationship Mdm2 p53 IC50 biology Chemistry Drug discovery Proto-Oncogene Proteins c-mdm2 Xenograft Model Antitumor Assays Rats Cell culture biology.protein Molecular Medicine Mdm2 Indicators and Reagents Tumor Suppressor Protein p53 |
| Zdroj: | Journal of Medicinal Chemistry. 57:2472-2488 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein. |
| Databáze: | OpenAIRE |
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