Identification of a Selective YTHDF1 Inhibitor Targeting the m<sup>6</sup>A Recognition Domain for Breast Cancer
Abstract
AbstractAs a key N6‐methyladenosine (m6A) reader, YTH domain‐containing family protein 1 (YTHDF1) promotes protein synthesis by recognizing m6A‐modified mRNA, and its abnormal expression is closely related to breast cancer (BC) progression. To date, the scarce reported YTHDF1 inhibitors suffer from poor selectivity and limited potency, primarily due to the high homology of the YTH domain within the YTHDF family, which poses significant challenges for the discovery of subtype‐selective inhibitors. Here, we report SKLB‐Y13, the first small‐molecule inhibitor achieving exclusive targeting of the YTHDF1 m6A‐binding pocket (IC50 = 0.76 µM), via structural optimization of a novel 4,5,6,7‐tetrahydrothieno[2,3‐c]pyridine scaffold. Uniquely, SKLB‐Y13 interacts with YTHDF1‐specific residues Tyr397 and Trp470, as confirmed by site‐directed mutagenesis, and demonstrates improved selectivity for YTHDF1 over YTH family proteins. Cellular and in vivo studies reveal that SKLB‐Y13 disrupts YTHDF1‐PRPF6 mRNA interaction in an m6A‐dependent manner, thereby impairing the translation of PRPF6 and inhibiting BC proliferation while promoting apoptosis. Chemical proteomics profiling confirms its good target specificity, while pharmacokinetic analysis shows favorable in vivo properties. This study introduces the first selective YTHDF1 inhibitor, serving as a novel chemical probe to elucidate m6A‐dependent oncogenesis and a promising starting point for developing precision therapies against YTHDF1‐overexpressing BC.
Article Details
Authors (10)
Yongya Wu
State Key Laboratory of Biotherapy and Cancer Center Innovation Center of Nursing Research Children's Medicine Key Laboratory of Sichuan Province West China Hospital Sichuan University No. 17, Section 3, Renmin South Road Chengdu 610041 China
Guotai Feng
State Key Laboratory of Biotherapy and Cancer Center Innovation Center of Nursing Research Children's Medicine Key Laboratory of Sichuan Province West China Hospital Sichuan University No. 17, Section 3, Renmin South Road Chengdu 610041 China
Wen Shuai
Xiao Yang
Xiaoli Pan
Chunyan Zhu
Frontiers Science Center for New Organic Matter, Key Laboratory of Advanced Energy Materials Chemistry (Ministry of Education), State Key Laboratory of Advanced Chemical Power Sources, College of Chemistry
Aoxue Wang
State Key Laboratory of Biotherapy and Cancer Center Innovation Center of Nursing Research Children's Medicine Key Laboratory of Sichuan Province West China Hospital Sichuan University No. 17, Section 3, Renmin South Road Chengdu 610041 China
Qiu Sun
Department of Cardiovascular Surgery, Cardiovascular Surgery Research Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University
Guan Wang
State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, National Center for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology
Liang Ouyang
Department of Cardiovascular Surgery, Cardiovascular Surgery Research Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University