Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction.
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.
Department of Therapeutic Discovery, ‡Department of Pharmaceutics, and §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
Yosup
Y
Rew
Daqing
D
Sun
Xuelei
X
Yan
Hilary P
HP
Beck
Jude
J
Canon
Ada
A
Chen
Jason
J
Duquette
John
J
Eksterowicz
Brian M
BM
Fox
Jiasheng
J
Fu
Ana Z
AZ
Gonzalez
Jonathan
J
Houze
Xin
X
Huang
Min
M
Jiang
Lixia
L
Jin
Yihong
Y
Li
Zhihong
Z
Li
Yun
Y
Ling
Mei-Chu
MC
Lo
Alexander M
AM
Long
Lawrence R
LR
McGee
Joel
J
McIntosh
Jonathan D
JD
Oliner
Tao
T
Osgood
Anne Y
AY
Saiki
Paul
P
Shaffer
Yu Chung
YC
Wang
Sarah
S
Wortman
Peter
P
Yakowec
Qiuping
Q
Ye
Dongyin
D
Yu
Xiaoning
X
Zhao
Jing
J
Zhou
Julio C
JC
Medina
Steven H
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Olson
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055808:Drug Discovery; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2