2. Academic Validation
  3. Discovery of 4-((3'R,4'S,5'R)-6″-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2″-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3″-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development

Discovery of 4-((3'R,4'S,5'R)-6″-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2″-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3″-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development

  • J Med Chem. 2017 Apr 13;60(7):2819-2839. doi: 10.1021/acs.jmedchem.6b01665.
Angelo Aguilar 1,  Jianfeng Lu 1,  Liu Liu 1,  Ding Du 1,  Denzil Bernard 1,  Donna McEachern 1,  Sally Przybranowski 1,  Xiaoqin Li 2,  Ruijuan Luo 2,  Bo Wen 2,  Duxin Sun 2,  Hengbang Wang 3 4,  Jianfeng Wen 3 4,  Guangfeng Wang 3 4,  Yifan Zhai 3 4,  Ming Guo 3 4,  Dajun Yang 3 4 5,  Shaomeng Wang 1
Affiliations

Affiliations

  • 1 University of Michigan Comprehensive Cancer Center, and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan , 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • 3 Jiangsu Ascentage Biomed Development Inc. , China Medical City, Taizhou, Jiangsu 225300, China.
  • 4 Suzhou Ascentage Pharma Inc. , Suzhou, Jiangsu 215123, China.
  • 5 Department of Experimental Research, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine , 651 Dongfeng Road East, Guangzhou, China.
PMID: 28339198 DOI: 10.1021/acs.jmedchem.6b01665
Abstract

We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure-activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (Ki < 1 nM), potent cellular activity, and an excellent oral pharmacokinetic profile. Compound 60 is capable of achieving complete and long-lasting tumor regression in vivo and is currently in phase I clinical trials for Cancer treatment.

Figures