2. Academic Validation
  3. Discovery of Novel Class of METTL3 Inhibitors with a Pyridin-2(1 H)‑one Moiety

Discovery of Novel Class of METTL3 Inhibitors with a Pyridin-2(1 H)‑one Moiety

  • ACS Med Chem Lett. 2025 Nov 4;16(11):2257-2263. doi: 10.1021/acsmedchemlett.5c00465.
Weihang Zhang 1,  Yuting Huang 2 3,  Hong Yang 2,  Haiyan Wan 4,  Xinsheng Lei 1,  Jinxi Xiang 2 5,  Yujie Wang 1,  Yingxia Li 1,  Xun Huang 2 3 5,  Yu Sun 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
  • 2 Lingang Laboratory, Shanghai 200031, P. R. China.
  • 3 School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 5 School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
PMID: 41257017 DOI: 10.1021/acsmedchemlett.5c00465
Abstract

N 6-Methyladenosine methylation (m6A) is the most common type of RNA modification and is catalyzed primarily by the METTL3-METTL14 methyltransferase complex. METTL3 is considered a promising target for the treatment of acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity have been developed recently. Herein we report a series of novel METTL3 inhibitors bearing a pyridin-2-(1H)-one moiety by structure-based drug design. Among these, compound 15 exhibits potent inhibitory activity against METTL3 (IC50 = 50 nM). Compound 15 shows moderate metabolic stability in mouse and human liver microsomes. Meanwhile, in MV411 and SKM1 cell lines, compound 15 is able to potently inhibit cell proliferation. These results make compound 15 a promising lead compound for further optimization.

Keywords

METTL3-METTL14 complex; Methyltransferase-like 3; conformational constraint; fragment growing; scaffold hopping.

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