Abstract MTAP deficiency is observed in approximately 15% of human cancers and leads to accumulation of methylthioadenosine (MTA), which competes with the methyl-donor S-adenosylmethionine (SAM) to partially inhibit post-translational methyltransferase activity of PRMT5. This molecular context creates a vulnerability in MTAP-deleted tumors, rendering them particularly susceptible to PRMT5 inhibition. MTA-cooperative PRMT5 inhibitors preferentially bind to PRMT5 when MTA occupies the SAM-binding pocket of PRMT5, thus increasing inhibitory specificity to MTAP-deficient cells. Here, we characterize ISM1745, a novel, orally bioavailable MTA-cooperative inhibitor. ISM1745 potently inhibits formation of symmetric dimethylarginine (SDMA), the PRMT5-catalyzed methylation product, and impairs cell growth in MTAP-deficient HCT116 cancer cells in vitro (IC50 = 1.1 nM), with 272-fold selectivity over MTAP wild-type HCT116 cells. In addition, Safety44 and methyltransferase panel screening indicated minimal off-target activity for ISM1745. Mechanistically, ISM1745 induces apoptosis, cell cycle arrest, and DNA damage specifically in MTAP-deleted cells, as indicated by an increased proportion of annexin V-positive cells, accumulation in the G1 phase, and elevated expression of DNA damage markers such as γH2AX. Once-daily oral administration of ISM1745 results in marked and sustained tumor growth inhibition in MTAP-deleted xenograft models. Moreover, when combined with ISM3412, an inhibitor of MAT2A, which catalyzes formation of SAM, ISM1745 exhibits significant synergistic anti-tumor activity, highlighting its promise as part of a combinatorial strategy for targeting MTAP-deficient cancers. In addition to its robust biological potency and high selectivity, ISM1745 exhibits favorable drug-like properties, including optimal in vitro ADMET profiles, excellent in vivo exposure, low clearance (CL30% Qh in non-rodent species), and moderate to high oral bioavailability across multiple preclinical species. Taken together, these findings support ISM1745 as a potent and selective MTA-cooperative PRMT5 inhibitor with robust anti-tumor efficacy, providing potential therapy for treatment of MTAP-deleted cancers. Citation Format: Yilin Yang, Zhongying Cao, Meng Zhang, Xiaoyu Ding, Hongfu Lu, Qingchuan Zhao, Xiaoxia Lin, Jiaojiao Yu, David Gennert, Suguna Rachakonda, Xiao Ding, Xin Cai, Man Zhang, Feng Ren, Alex Zhavoronkov. ISM1745, an MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7077.
Yang et al. (Fri,) studied this question.