Discovery of AMG 232, a Potent,
Selective, and Orally
Bioavailable MDM2–p53 Inhibitor in Clinical Development
Daqing Sun
Zhihong Li
Yosup Rew
Michael Gribble
Michael
D. Bartberger
Hilary P. Beck
Jude Canon
Ada Chen
Xiaoqi Chen
David Chow
Jeffrey Deignan
Jason Duquette
John Eksterowicz
Benjamin Fisher
Brian M. Fox
Jiasheng Fu
Ana Z. Gonzalez
Felix Gonzalez-Lopez De Turiso
Jonathan B. Houze
Xin Huang
Min Jiang
Lixia Jin
Frank Kayser
Jiwen
(Jim) Liu
Mei-Chu Lo
Alexander M. Long
Brian Lucas
Lawrence
R. McGee
Joel McIntosh
Jeff Mihalic
Jonathan D. Oliner
Tao Osgood
Matthew
L. Peterson
Philip Roveto
Anne Y. Saiki
Paul Shaffer
Maria Toteva
Yingcai Wang
Yu Chung Wang
Sarah Wortman
Peter Yakowec
Xuelei Yan
Qiuping Ye
Dongyin Yu
Ming Yu
Xiaoning Zhao
Jing Zhou
Jiang Zhu
Steven
H. Olson
Julio C. Medina
10.1021/jm401753e.s001
https://acs.figshare.com/articles/journal_contribution/Discovery_of_AMG_232_a_Potent_Selective_and_Orally_Bioavailable_MDM2_p53_Inhibitor_in_Clinical_Development/2319247
We
recently reported the discovery of AM-8553 (<b>1</b>),
a potent and selective piperidinone inhibitor of the MDM2–p53
interaction. Continued research investigation of the <i>N</i>-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 (<b>2</b>), which is currently
being evaluated in human clinical trials for the treatment of cancer.
Compound <b>2</b> is an extremely potent MDM2 inhibitor (SPR <i>K</i><sub>D</sub> = 0.045 nM, SJSA-1 EdU IC<sub>50</sub> = 9.1
nM), with remarkable pharmacokinetic properties and in vivo antitumor
activity in the SJSA-1 osteosarcoma xenograft model (ED<sub>50</sub> = 9.1 mg/kg).
2014-02-27 00:00:00
0.045 nM
SPR KD
Clinical DevelopmentWe
SJSA
EdU IC 50
osteosarcoma xenograft model
AMG
pharmacokinetic properties
9.1
ED 50
MDM 2 surface
research investigation
AM
MDM 2 inhibitor
piperidinone inhibitor
interaction
vivo antitumor activity
Compound 2