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

  • ACS Med Chem Lett. 2025 Jun 27;16(7):1313-1322. doi: 10.1021/acsmedchemlett.5c00185.
Yuxin Yang  1  2 ,  Zonglong Chen  1 ,  Yujie Wang  1 ,  Xun Huang  3  4  5  6 ,  Chun Hu  2 ,  Hong Yang  3 ,  Yingxia Li  1
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
  • 2. Department of Medicinal Chemistry, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
  • 3. Lingang Laboratory, Shanghai 200031, P. R. China.
  • 4. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 5. School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 6. School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
PMID: 40666447 DOI: 10.1021/acsmedchemlett.5c00185
Abstract

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.

Keywords
PRMT5·MTA complex; Protein arginine methyltransferase 5; inhibitor; structure-based drug design; synthetic lethality.
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