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

• Published in: MedComm (2020) 2024-10, Vol.5 (10), p.e705-n/a
• Main Authors: Yu, Zhiyong, Kuang, Yi, Xue, Liting, Ma, Xuan, Li, Tingting, Yuan, Linlin, Li, Mengying, Xue, Grace, Li, Zhen, Tang, Feng, Tang, Jianxing, Shan, Jinwen, Wang, Weijie, Tang, Renhong, Zhou, Feng
• Format: Article
• Language: English
• Subjects: Cancer; drug combination; MAT2A inhibitor; Metabolism; MTAP‐deleted cancer; PRMT5
• ISSN: 2688-2663; 2688-2663
• DOI: 10.1002/mco2.705

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. We discovered a potent and specific allosteric MAT2A inhibitor SCR‐7952. SCR‐7952 selectively inhibited the growth of MTAP‐deleted cancers, via the regulation of PRMT5 activity. The cryo‐EM indicated an allosteric binding site. Furthermore, the combination of SCR‐7952 with SAM‐competitive or MTA‐cooperative PRMT5 inhibitors supported further investigation and potential development of an effective strategy for larger therapeutic windows on MTAP‐deleted cancers.