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Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction.

Abstract
Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.
AuthorsYosup Rew, Daqing Sun, Xuelei Yan, Hilary P Beck, Jude Canon, Ada Chen, Jason Duquette, John Eksterowicz, Brian M Fox, Jiasheng Fu, Ana Z Gonzalez, Jonathan Houze, Xin Huang, Min Jiang, Lixia Jin, Yihong Li, Zhihong Li, Yun Ling, Mei-Chu Lo, Alexander M Long, Lawrence R McGee, Joel McIntosh, Jonathan D Oliner, Tao Osgood, Anne Y Saiki, Paul Shaffer, Yu Chung Wang, Sarah Wortman, Peter Yakowec, Qiuping Ye, Dongyin Yu, Xiaoning Zhao, Jing Zhou, Julio C Medina, Steven H Olson
JournalJournal of medicinal chemistry (J Med Chem) Vol. 57 Issue 24 Pg. 10499-511 (Dec 26 2014) ISSN: 1520-4804 [Electronic] United States
PMID25384157 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
Topics
  • Animals
  • Antineoplastic Agents (chemistry, pharmacology)
  • Cell Proliferation (drug effects)
  • Colonic Neoplasms (drug therapy, metabolism, pathology)
  • Drug Discovery
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Protein Binding (drug effects)
  • Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 (antagonists & inhibitors, metabolism)

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