2. Academic Validation
  3. Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy

Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy

  • J Med Chem. 2024 Jun 13;67(11):9431-9446. doi: 10.1021/acs.jmedchem.4c00552.
Faridoon 1,  Jiyue Zheng 1,  Tao Zhang 1,  Shuilong Tong 1,  Tao Liu 1,  Jiuen Cui 1,  Haojie Xu 1,  Di Hu 1,  Ying Shen 1,  Yajing Yin 1,  Danhua Zhao 1,  Chensheng Tan 1,  Xue Dong 1,  Jiali Chen 1,  Feihong Ji 1,  Chenhua Tong 1,  Jie Jack Li 1,  Jiapeng Li 1,  Guiping Zhang 1
Affiliations

Affiliation

  • 1 Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
PMID: 38818879 DOI: 10.1021/acs.jmedchem.4c00552
Abstract

Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise Anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-c]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound 39, which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted Cancer cell lines. Compound 39 has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, 39 demonstrates excellent brain exposure with a Kpuu of 0.64 in rats.

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