Structure-Guided Discovery of Novel Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitors

Methylthioadenosine (MTA) accumulation inhibits the protein arginine methyltransferase 5 (PRMT5), rendering cancers harboring methylthioadenosine phosphorylase (MTAP) deletion vulnerable; thus, PRMT5 inhibitors hold promise for treating these cancers. In this letter, a structure-guided design approach yielded many novel highly potent and selective MTA-cooperative PRMT5 inhibitors featuring a core structure of 4-amino-N-((5-ethynylpyridin-2-yl)-methyl)-1-methyl-1H-pyrazolo-[4,3-c]-quinoline-8-carboxamide. Among them, compound 27 demonstrated significant inhibitory activity and selectivity against HCT116 MTAP-del cells. Further biological evaluations demonstrated that this compound exerts potent inhibitory effects across multiple MTAP-null cancer cell lines, alongside robust enzymatic inhibition and favorable pharmacokinetic profiles consistent with drug-like properties. Notably, compound 27 displayed prominent in vivo antitumor potency in a HCT116 MTAP^-/^- CDX model. Collectively, these results establish compound 27 as a highly effective and selective MTA-cooperative PRMT5 inhibitor, presenting a promising candidate for future therapeutic development.