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

Angelo Aguilar; Jianfeng Lu; Liu Liu; Ding Du; Denzil Bernard; Donna McEachern; Sally Przybranowski; Xiaoqin Li; Ruijuan Luo; Bo Wen; Duxin Sun; Hengbang Wang; Jianfeng Wen; Guangfeng Wang; Yifan Zhai; Ming Guo; Dajun Yang; Shaomeng Wang

doi:10.1021/acs.jmedchem.6b01665

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. Epub 2017 Mar 24.

Authors

Angelo Aguilar¹, Jianfeng Lu¹, Liu Liu¹, Ding Du¹, Denzil Bernard¹, Donna McEachern¹, Sally Przybranowski¹, Xiaoqin Li², Ruijuan Luo², Bo Wen², Duxin Sun², 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 Wang¹

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.

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 (K_i < 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Bone Neoplasms / drug therapy
Bone Neoplasms / metabolism
Bone Neoplasms / pathology
Bone and Bones / drug effects
Bone and Bones / metabolism
Bone and Bones / pathology
Bridged Bicyclo Compounds / chemistry
Bridged Bicyclo Compounds / pharmacokinetics
Bridged Bicyclo Compounds / pharmacology
Bridged Bicyclo Compounds / therapeutic use
Cell Line, Tumor
Drug Discovery*
Halogenation
Humans
Indoles / chemistry
Indoles / pharmacokinetics
Indoles / pharmacology
Indoles / therapeutic use
Leukemia / drug therapy
Leukemia / metabolism
Leukemia / pathology
Mice
Molecular Docking Simulation
Neoplasms / drug therapy*
Neoplasms / metabolism
Neoplasms / pathology
Osteosarcoma / drug therapy
Osteosarcoma / metabolism
Osteosarcoma / pathology
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-mdm2 / metabolism
Pyrrolidines / chemistry*
Pyrrolidines / pharmacokinetics
Pyrrolidines / pharmacology
Pyrrolidines / therapeutic use*
Rats
Structure-Activity Relationship

Substances

Antineoplastic Agents
Bridged Bicyclo Compounds
Indoles
Pyrrolidines
indoline
Proto-Oncogene Proteins c-mdm2

Abstract

Publication types

MeSH terms

Substances

Grants and funding