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
  • 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.