LAUSR

MTAP deletion is common in about 15% of all human cancers and coincides with the deletion of tumor suppressor locus containing CDKN2A/B. Methylthioadenosine (MTA), the substrate of MTAP, accumulates as a result of MTAP deletion. Increased levels of MTA result in partial inhibition of the PRMT5 enzyme by competing with S-adenosylmethionine (SAM, the methyl donor for PRMT5 substrate) due to structural similarity. Cancer cell lines with MTAP-deletion exhibit profound sensitivity to PRMT5 inhibition, suggesting MTAPnull-selective PRMT5 inhibitors have the potential to treat patients with MTAP deficiency (Kryukov et al., 2016). We identified CTS3157 as an orally bioavailable small molecule MTA-cooperative PRMT5 inhibitor that binds to PRMT5-MTA complex and inhibits PRMT5 enzymatic activity. Cell-based assays revealed that CTS3157 demonstrated potent PRMT5 inhibition as evidenced by suppression of symmetric dimethylarginine (SDMA) and cell growth inhibitory activity for MTAP-deleted cell lines over isogenic MTAPWT cell lines. Moreover, CTS3157 series compounds exhibited strong cell growth inhibition in a diverse panel of MTAPnull human tumor cell lines across several lineages. In vivo, CTS3157 demonstrated potent antitumor response after once-daily oral administration in MTAP-deleted xenograft models. The anti-tumor activity is correlated with PRMT5 modulation as measured by reduced SDMA levels. At molecular level, PRMT5 inhibition by CTS3157 resulted in massive RNA splicing defects and differentially expressed genes involving key cellular activities in MTAPnull cells. In summary, MTAPnull-selective PRMT5 inhibitor CTS3157 showed strong and durable antitumor responses in vitro and in vivo in MTAP-deleted tumors across diverse lineages. CTS3157 is an effective and promising therapeutics against MTAP-deleted tumors. Citation Format: Long Wang, Yilin Liu, Hui Shi, Yuanyuan Liu, Qiugeng Ouyang, Jiannan Guo, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting MTAP-deleted human tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6273.