1. Academic Validation
  2. SCR-7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative protein arginine methyltransferase 5 inhibitors in methylthioadenosine phosphorylase-deleted tumors

SCR-7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative protein arginine methyltransferase 5 inhibitors in methylthioadenosine phosphorylase-deleted tumors

  • MedComm (2020). 2024 Sep 20;5(10):e705. doi: 10.1002/mco2.705.
Zhiyong Yu 1 2 Yi Kuang 2 Liting Xue 1 2 Xuan Ma 3 Tingting Li 2 Linlin Yuan 1 Mengying Li 2 Grace Xue 4 Zhen Li 2 Feng Tang 1 Jianxing Tang 2 Jinwen Shan 2 Weijie Wang 3 Renhong Tang 1 2 Feng Zhou 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Neurology and Oncology Drug Development Nanjing China.
  • 2 Department of Preclinical Research Simcere Zaiming Pharmaceutical Co., Ltd. Shanghai China.
  • 3 Department of Thoracic Surgery The Affiliated Xiangshan Hospital of Wenzhou Medical University Wenzhou Zhejiang China.
  • 4 Weston High School Weston Massachusetts USA.
Abstract

The metabolic Enzyme methionine adenosyltransferase 2A (MAT2A) was found to elicit synthetic lethality in methylthioadenosine phosphorylase (MTAP)-deleted cancers, which occur in about 15% of all cancers. Here, we described a novel MAT2A inhibitor, SCR-7952 with potent and selective antitumor effects on MTAP-deleted cancers in both in vitro and in vivo. The cryo-EM data indicated the high binding affinity and the allosteric binding site of SCR-7952 on MAT2A. Different from AG-270, SCR-7952 exhibited little influence on metabolic Enzymes and did not increase the plasma levels of bilirubin. A systematic evaluation of combination between SCR-7952 and different types of protein arginine methyltransferase 5 (PRMT5) inhibitors indicated remarkable synergistic interactions between SCR-7952 and the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative PRMT5 inhibitors, but not substrate-competitive ones. The mechanism was via the aggravated inhibition of PRMT5 and FANCA splicing perturbations. These results indicated that SCR-7952 could be a potential therapeutic candidate for the treatment of MTAP-deleted cancers, both monotherapy and in combination with PRMT5 inhibitors.

Keywords

MAT2A inhibitor; MTAP‐deleted cancer; PRMT5; drug combination.

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