2. Academic Validation
  3. Discovery of a PROTAC degrader for METTL3-METTL14 complex

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

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: xhuang@lglab.ac.cn.
  • 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: slxu@simm.ac.cn.
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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