Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development.
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
Departments of Therapeutic Discovery, ‡Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California, 94080, United States.
Daqing
D
Sun
Zhihong
Z
Li
Yosup
Y
Rew
Michael
M
Gribble
Michael D
MD
Bartberger
Hilary P
HP
Beck
Jude
J
Canon
Ada
A
Chen
Xiaoqi
X
Chen
David
D
Chow
Jeffrey
J
Deignan
Jason
J
Duquette
John
J
Eksterowicz
Benjamin
B
Fisher
Brian M
BM
Fox
Jiasheng
J
Fu
Ana Z
AZ
Gonzalez
Felix
F
Gonzalez-Lopez De Turiso
Jonathan B
JB
Houze
Xin
X
Huang
Min
M
Jiang
Lixia
L
Jin
Frank
F
Kayser
Jiwen Jim
JJ
Liu
Mei-Chu
MC
Lo
Alexander M
AM
Long
Brian
B
Lucas
Lawrence R
LR
McGee
Joel
J
McIntosh
Jeff
J
Mihalic
Jonathan D
JD
Oliner
Tao
T
Osgood
Matthew L
ML
Peterson
Philip
P
Roveto
Anne Y
AY
Saiki
Paul
P
Shaffer
Maria
M
Toteva
Yingcai
Y
Wang
Yu Chung
YC
Wang
Sarah
S
Wortman
Peter
P
Yakowec
Xuelei
X
Yan
Qiuping
Q
Ye
Dongyin
D
Yu
Ming
M
Yu
Xiaoning
X
Zhao
Jing
J
Zhou
Jiang
J
Zhu
Steven H
SH
Olson
Julio C
JC
Medina
D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
C588087:2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; D000085:Acetates; D000970:Antineoplastic Agents; D010881:Piperidones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2