ISM1745：一种用于治疗MTAP缺失型癌症的MTA协同性PRMT5抑制剂

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 gammaH2AX. 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 (CL<30% 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.