Abstract 6977: Development of SY-9453, a novel MAT2A inhibitor, for the treatment of MTAP-deficient cancers

Abstract Co-deletion of the MTAP gene with the CDKN2A gene, which is found in approximately 15% of all cancers, results in sensitization to MAT2A inhibition and provides an option for therapeutic intervention. The encouraging clinical activity of IDE397 provides further proof-of-concept for MAT2A inhibitors in the treatment of MTAP-deficient cancers. Here, we describe SY-9453 as a novel and potent MAT2A inhibitor. In the biochemical assay, SY-9453 potently inhibited the activity of MAT2A enzyme with an IC50 of 0.5 nM. In HCT116 MTAP-/- cells, SY-9453 showed very strong inhibition of the cellular SAM production and protein SDMA modification with IC50s less than 10 nM. Moreover, SY-9453 also demonstrated strong inhibitory activity on the proliferation of multiple MTAP-deficient cancer cell lines. Functionally, SY-9453 reduced cellular mRNA splicing, induced cell cycle arrest, and promoted cell apoptosis in a dose-dependent manner. In vivo studies showed that SY-9453 has robust anti-tumor activity in several CDX models of colorectal cancer, pancreatic cancer, and non-small cell lung cancer. In the HCT116 MTAP-/- xenograft model, SY-9453 displayed dose-dependent inhibition of tumor growth, and tumor regression was observed after treatment with SY-9453 at 25 mpk, QD. Furthermore, SY-9453 revealed favorable PK properties and tolerability in preclinical studies. In conclusion, the current results demonstrate that SY-9453 is a novel small molecule MAT2A inhibitor with high activity in vitro and in vivo, providing a rational option for treating cancers with MTAP deficiency. Citation Format: Shuang Liu, Zhenbang Lou, Ying Xin, Chang Lu, Shikang Cheng, Junfen Shi, Yeliu Wang, Sheng Zhao, Yan Zhu, Hong Luo, Yinghui Sun. Development of SY-9453, a novel MAT2A inhibitor, for the treatment of MTAP-deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6977.