Discovery of Novel MTA-Cooperative PRMT5 Inhibitors with a 2,3-Dihydro-1<i>H</i>-imidazo[1,2-<i>b</i>]pyrazole Scaffold
Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a synthetically lethal target in methylthioadenosine phosphorylase (<i>MTAP</i>)-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-1<i>H</i>-imidazo-[1,2-<i>b</i>]-pyrazole scaffold by structure-based drug design. Among these, compound <b>31</b> exhibits potent inhibitory activity against PRMT5·MTA (IC<sub>50</sub> = 6.6 nM) with 339-fold selectivity against PRMT5 while selectively inhibiting cell growth in <i>MTAP</i>-deleted HCT-116 cells (IC<sub>50</sub> = 319 nM) compared to <i>MTAP</i>-wild-type cells. These results make compound <b>31</b> a promising lead compound for further optimization.
Authors
- Chun Hu (ORCID: https://orcid.org/0000-0003-2919-2870)
- Hong Yang (ORCID: https://orcid.org/0000-0003-1250-5156)
- Yingxia Li (ORCID: https://orcid.org/0000-0001-6782-8740)
- Zonglong Chen (ORCID: https://orcid.org/0000-0003-4733-8255)
- Xun Huang (ORCID: https://orcid.org/0000-0002-2653-8293)
- Yuxin Yang (ORCID: https://orcid.org/0000-0002-3016-4167)
- Yujie Wang (ORCID: https://orcid.org/0009-0009-2732-1991)
Institutions
- Shenyang Pharmaceutical University (CN)
- Nanjing University of Chinese Medicine (CN)
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- ShanghaiTech University (CN)
- Indiana University School of Medicine
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00185
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Program of Shanghai Subject Chief Scientist