2. Academic Validation
  3. Structure-Based Discovery of a Series of Novel MAT2a Inhibitors

Structure-Based Discovery of a Series of Novel MAT2a Inhibitors

  • ACS Med Chem Lett. 2025 Mar 15;16(4):646-650. doi: 10.1021/acsmedchemlett.5c00049.
Yushan Zhou 1 2 3,  Li Wang 4 5,  Ruyue Ren 2 3 6,  Junjie Zhang 2 3 5,  Xiajuan Huan 4,  Peng Yang 1,  Ze-Hong Miao 4 5,  Bing Xiong 2 3 5,  Yingqing Wang 4 5,  Tongchao Liu 2 3
Affiliations

Affiliations

  • 1 Wuya College of Innovation, Shenyang Pharmaceutical University,103 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
  • 2 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
  • 4 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, P. R. China.
  • 5 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China.
  • 6 School of Pharmacy, Shanxi Medical University, Taiyuan 030001, P. R. China.
PMID: 40236535 DOI: 10.1021/acsmedchemlett.5c00049
Abstract

Methionine adenosyltransferase 2a (MAT2a) has emerged as a promising therapeutic target due to its role in the synthetic lethality mechanism associated with MTAP-deficient tumors. In this study, we describe our efforts to identify a novel series of MAT2a inhibitors through a fragment-based joining strategy, leading to the development of a single molecule that occupies the allosteric site of the MAT2a dimer. Guided by the costructure of AZ-28 in complex with the MAT2a dimer, compound 9 was synthesized, demonstrating potent MAT2a inhibition (IC50 = 20 nM) and significantly enhanced antiproliferative activity (IC50 = 10 nM against HAP1MTAP-/- cells). Moreover, compound 9 exhibited improved selectivity compared to both AZ-28 and AG-270.

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