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
Zhiyong Yu,
Yi Kuang,
Liting Xue,
Xuan Ma,
Tingting Li,
Linlin Yuan,
Mengying Li,
Grace Xue,
Zhen Li,
Feng Tang,
Jianxing Tang,
Jinwen Shan,
Weijie Wang,
Renhong Tang,
Feng Zhou
Affiliations
Zhiyong Yu
State Key Laboratory of Neurology and Oncology Drug DevelopmentNanjingChina
Yi Kuang
Department of Preclinical ResearchSimcere Zaiming Pharmaceutical Co., Ltd.Shanghai China
Liting Xue
State Key Laboratory of Neurology and Oncology Drug DevelopmentNanjingChina
Xuan Ma
Department of Thoracic SurgeryThe Affiliated Xiangshan Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
Tingting Li
Department of Preclinical ResearchSimcere Zaiming Pharmaceutical Co., Ltd.Shanghai China
Linlin Yuan
State Key Laboratory of Neurology and Oncology Drug DevelopmentNanjingChina
Mengying Li
Department of Preclinical ResearchSimcere Zaiming Pharmaceutical Co., Ltd.Shanghai China
Grace Xue
Weston High SchoolWestonMassachusettsUSA
Zhen Li
Department of Preclinical ResearchSimcere Zaiming Pharmaceutical Co., Ltd.Shanghai China
Feng Tang
State Key Laboratory of Neurology and Oncology Drug DevelopmentNanjingChina
Jianxing Tang
Department of Preclinical ResearchSimcere Zaiming Pharmaceutical Co., Ltd.Shanghai China
Jinwen Shan
Department of Preclinical ResearchSimcere Zaiming Pharmaceutical Co., Ltd.Shanghai China
Weijie Wang
Department of Thoracic SurgeryThe Affiliated Xiangshan Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
Renhong Tang
State Key Laboratory of Neurology and Oncology Drug DevelopmentNanjingChina
Feng Zhou
State Key Laboratory of Neurology and Oncology Drug DevelopmentNanjingChina
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.
