Discovery of a PROTAC degrader for METTL3-METTL14 complex

  • Cell Chem Biol. 2024 Jan 18;31(1):177-183.e17. doi: 10.1016/j.chembiol.2023.12.009.
Wenhao Du  1 ,  Yuting Huang  2 ,  Xiaoai Chen  1 ,  Yue Deng  3 ,  Yaoliang Sun  4 ,  Hong Yang  5 ,  Qiongyu Shi  6 ,  Feifei Wu  7 ,  Guobin Liu  8 ,  He Huang  9 ,  Jian Ding  3 ,  Xun Huang  10 ,  Shilin Xu  11
Affiliations
  • 1. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 2. Lingang Laboratory, Shanghai 200031, China; School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 3. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Science, Beijing 100049, China.
  • 4. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5. Lingang Laboratory, Shanghai 200031, China; Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6. Lingang Laboratory, Shanghai 200031, China.
  • 7. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Science, Beijing 100049, China.
  • 8. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 9. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 10. Lingang Laboratory, Shanghai 200031, China; Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Science, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: [email protected].
  • 11. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; University of Chinese Academy of Science, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: [email protected].
PMID: 38194973 DOI: 10.1016/j.chembiol.2023.12.009
Abstract

N6-methyladenosine (m6A) methylation is the most abundant type of RNA modification that is mainly catalyzed by the METTL3-METTL14 methyltransferase complex. This complex has been linked to multiple cancers and is considered a promising therapeutic target for acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity were developed recently. Here, we present the discovery of WD6305 as the potent and selective proteolysis-targeting chimera (PROTAC) degrader of METTL3-METTL14 complex. WD6305 suppresses m6A modification and the proliferation of AML cells, and promotes Apoptosis much more effectively than its parent inhibitor. WD6305 also affects a variety of signaling pathways related to the development and proliferation of AML. Collectively, our study reveals PROTAC degradation of METTL3-METTL14 complex as a potential anti-leukemic strategy and provides desirable chemical tool for further understanding METTL3-METTL14 protein functions.

Keywords
Degrader; METTL3; Methyltransferase; PROTAC; m(6)A.
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