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.
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.
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.
Angelo
A
Aguilar
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.
Jianfeng
J
Lu
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.
Liu
L
Liu
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.
Ding
0000-0002-4615-5433
D
Du
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.
Denzil
D
Bernard
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.
Donna
D
McEachern
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.
Sally
S
Przybranowski
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
Xiaoqin
X
Li
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
Ruijuan
R
Luo
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
Bo
B
Wen
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
Duxin
D
Sun
Jiangsu Ascentage Biomed Development Inc. , China Medical City, Taizhou, Jiangsu 225300, China.|Suzhou Ascentage Pharma Inc. , Suzhou, Jiangsu 215123, China.
Hengbang
H
Wang
Jiangsu Ascentage Biomed Development Inc. , China Medical City, Taizhou, Jiangsu 225300, China.|Suzhou Ascentage Pharma Inc. , Suzhou, Jiangsu 215123, China.
Jianfeng
J
Wen
Jiangsu Ascentage Biomed Development Inc. , China Medical City, Taizhou, Jiangsu 225300, China.|Suzhou Ascentage Pharma Inc. , Suzhou, Jiangsu 215123, China.
Guangfeng
G
Wang
Jiangsu Ascentage Biomed Development Inc. , China Medical City, Taizhou, Jiangsu 225300, China.|Suzhou Ascentage Pharma Inc. , Suzhou, Jiangsu 215123, China.
Yifan
Y
Zhai
Jiangsu Ascentage Biomed Development Inc. , China Medical City, Taizhou, Jiangsu 225300, China.|Suzhou Ascentage Pharma Inc. , Suzhou, Jiangsu 215123, China.
Ming
M
Guo
Jiangsu Ascentage Biomed Development Inc. , China Medical City, Taizhou, Jiangsu 225300, China.|Suzhou Ascentage Pharma Inc. , Suzhou, Jiangsu 215123, China.|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.
Dajun
D
Yang
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.
Shaomeng
0000-0002-8782-6950
S
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D055808:Drug Discovery; D054879:Halogenation; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D007211:Indoles; D011759:Pyrrolidines; C057812:indoline; D051736:Proto-Oncogene Proteins c-mdm2