2. Academic Validation
  3. Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction

Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction

  • J Med Chem. 2014 Dec 26;57(24):10499-511. doi: 10.1021/jm501550p.
Yosup Rew 1,  Daqing Sun,  Xuelei Yan,  Hilary P Beck,  Jude Canon,  Ada Chen,  Jason Duquette,  John Eksterowicz,  Brian M Fox,  Jiasheng Fu,  Ana Z Gonzalez,  Jonathan Houze,  Xin Huang,  Min Jiang,  Lixia Jin,  Yihong Li,  Zhihong Li,  Yun Ling,  Mei-Chu Lo,  Alexander M Long,  Lawrence R McGee,  Joel McIntosh,  Jonathan D Oliner,  Tao Osgood,  Anne Y Saiki,  Paul Shaffer,  Yu Chung Wang,  Sarah Wortman,  Peter Yakowec,  Qiuping Ye,  Dongyin Yu,  Xiaoning Zhao,  Jing Zhou,  Julio C Medina,  Steven H Olson
Affiliations

Affiliation

  • 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.
PMID: 25384157 DOI: 10.1021/jm501550p
Abstract

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z