Discovery of Novel MTA-Cooperative PRMT5 Inhibitors with a 2,3-Dihydro‑1H‑imidazo[1,2‑b]pyrazole Scaffold.

Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a synthetically lethal target in methylthioadenosine phosphorylase (MTAP)-deficient tumors due to the formation of the PRMT5·MTA complex. Herein we report a series of novel PRMT5·MTA inhibitors bearing a 2,3-dihydro-1H-imidazo-[1,2-b]-pyrazole scaffold by structure-based drug design. Among these, compound 31 exhibits potent inhibitory activity against PRMT5·MTA (IC50 = 6.6 nM) with 339-fold selectivity against PRMT5 while selectively inhibiting cell growth in MTAP-deleted HCT-116 cells (IC50 = 319 nM) compared to MTAP-wild-type cells. These results make compound 31 a promising lead compound for further optimization.