Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction

  • J Med Chem. 2014 Mar 27;57(6):2472-88. doi: 10.1021/jm401767k.
Ana Z Gonzalez  1 ,  John Eksterowicz ,  Michael D Bartberger ,  Hilary P Beck ,  Jude Canon ,  Ada Chen ,  David Chow ,  Jason Duquette ,  Brian M Fox ,  Jiasheng Fu ,  Xin Huang ,  Jonathan B Houze ,  Lixia Jin ,  Yihong Li ,  Zhihong Li ,  Yun Ling ,  Mei-Chu Lo ,  Alexander M Long ,  Lawrence R McGee ,  Joel McIntosh ,  Dustin L McMinn ,  Jonathan D Oliner ,  Tao Osgood ,  Yosup Rew ,  Anne Y Saiki ,  Paul Shaffer ,  Sarah Wortman ,  Peter Yakowec ,  Xuelei Yan ,  Qiuping Ye ,  Dongyin Yu ,  Xiaoning Zhao ,  Jing Zhou ,  Steven H Olson ,  Julio C Medina ,  Daqing Sun
Affiliations
  • 1. Departments of †Therapeutic Discovery, ‡Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
PMID: 24548297 DOI: 10.1021/jm401767k
Abstract

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.

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