2. Academic Validation
  3. Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction

Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction

  • J Med Chem. 2014 Mar 27;57(6):2472-88. doi: 10.1021/jm401767k.
Ana Z Gonzalez 1,  John Eksterowicz,  Michael D Bartberger,  Hilary P Beck,  Jude Canon,  Ada Chen,  David Chow,  Jason Duquette,  Brian M Fox,  Jiasheng Fu,  Xin Huang,  Jonathan B Houze,  Lixia Jin,  Yihong Li,  Zhihong Li,  Yun Ling,  Mei-Chu Lo,  Alexander M Long,  Lawrence R McGee,  Joel McIntosh,  Dustin L McMinn,  Jonathan D Oliner,  Tao Osgood,  Yosup Rew,  Anne Y Saiki,  Paul Shaffer,  Sarah Wortman,  Peter Yakowec,  Xuelei Yan,  Qiuping Ye,  Dongyin Yu,  Xiaoning Zhao,  Jing Zhou,  Steven H Olson,  Julio C Medina,  Daqing Sun
Affiliations

Affiliation

  • 1 Departments of †Therapeutic Discovery, ‡Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
PMID: 24548297 DOI: 10.1021/jm401767k
Abstract

We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.

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