Discovery of a PROTAC degrader for METTL3-METTL14 complex

Wenhao Du; Yuting Huang; Xiaoai Chen; Yue Deng; Yaoliang Sun; Hong Yang; Qiongyu Shi; Feifei Wu; Guobin Liu; He Huang; Jian Ding; Xun Huang; Shilin Xu

doi:10.1016/j.chembiol.2023.12.009

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. Epub 2024 Jan 8.

Authors

Wenhao Du¹, Yuting Huang², Xiaoai Chen¹, Yue Deng³, Yaoliang Sun⁴, Hong Yang⁵, Qiongyu Shi⁶, Feifei Wu⁷, Guobin Liu⁸, He Huang⁹, Jian Ding³, Xun Huang¹⁰, Shilin Xu¹¹

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine*
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Methylation
Methyltransferases / genetics
Methyltransferases / metabolism

Substances

Adenosine
Methyltransferases
METTL3 protein, human
METTL14 protein, human