Abstract
Abstract Background: MAT2A (Methionine adenosyltransferase 2A) catalyzes the formation of S-adenosylmethionine (SAM) from methionine and ATP. PRMT5, a highly conserved protein arginine methyltransferase that is required for cell proliferation, uses SAM as its methyl donor. PRMT5 activity is inhibited by increased MTA levels in methylthioadenosine phosphorylase (MTAP)-deleted tumor cells. MTAP-deleted tumor cells are thus more vulnerable to MAT2A inhibition compared to MTAP-WT cells. This synthetic lethality between MTAP and MAT2A suggests that MAT2A inhibitors may be useful as anti-tumor agents in the MTAP-deleted cancers, which occurs in ~ 15% of all cancers. Results: We have designed, synthesized and evaluated a novel series of small-molecule MAT2A inhibitors that are very potent in biochemical assays. Co-crystal structures of inhibitor-MAT2A complexes were solved and shed light on binding mode and key interactions. Biochemical mechanistic studies suggested that these compounds are allosteric inhibitors of MAT2A and are non-competitive inhibitors of MAT2A with respect to both ATP and methionine. These compounds displayed potent cellular anti-proliferation activity as well as cellular SAM modulation along with desired DMPK properties. Optimized compounds, upon oral dosing, demonstrated significant PD marker modulation and tumor growth inhibition in HCT116 MTAP-null and several endogenous MTAP-null xenograft mouse models. These agents demonstrated an acceptable safety profile in 7-day oral repeat dose tolerability studies in the rat. Citation Format: Zhonghua Pei, Muzaffar Alam, Neil Bhola, Leah Cleary, Jake Drummond, Marcus Fisher, Melissa Fleury, Candy Garcia, Atieh Givmanesh, Xin Linghu, Ethan McSpadden, Zineb Mounir, Claire Neilan, Zach Newby, Senthil Perumal, Richard Steel, James Sutton, Kedar Vaidya, Marie-Claire Wagle, Jianhong Wang, Bing Yao, Mark Lackner, Michael P. Dillon. In vitro and in vivo characterization of novel MAT2A allosteric inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1956.
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