Discovery of a potent PROTAC degrader for RNA demethylase FTO as antileukemic therapy.

Lu LIU; Yuanlai QIU; Yuying SUO; Siyao TONG; Yiqing WANG; Xi ZHANG; Liang CHEN; Yue HUANG; Huchen ZHOU; Hu ZHOU; Ze DONG; Cai-Guang YANG

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Discovery of a potent PROTAC degrader for RNA demethylase FTO as antileukemic therapy.

Author: Lu LIU ¹ ; Yuanlai QIU ¹ ; Yuying SUO ² ; Siyao TONG ¹ ; Yiqing WANG ¹ ; Xi ZHANG ¹ ; Liang CHEN ² ; Yue HUANG ¹ ; Huchen ZHOU ³ ; Hu ZHOU ¹ ; Ze DONG ¹ ; Cai-Guang YANG ¹
Author Information

1. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3. State Key Laboratory of Microbial Metabolism, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Publication Type:Journal Article
Keywords: Antileukemia; FTO; N6-Methyladenosine; PROTAC; RNA epigenetics
From: Acta Pharmaceutica Sinica B 2024;14(12):5382-5392
CountryChina
Language:English
Abstract: The fat mass and obesity-associated protein (FTO) is an RNA demethylase required for catalytic demethylation of N ⁶-methyladenosine (m⁶A); it is highly expressed and functions as an oncogene in acute myeloid leukemia (AML). Currently, the overarching objective of targeting FTO is to precisely inhibit the catalytic activity. Meanwhile, whether FTO degradation also exerts antileukemic effects remains unknown. Herein, we designed the first FTO-targeting proteolysis targeting chimera (PROTAC) degrader QP73 using our FTO inhibitor Dac85-which potently inhibits FTO demethylation in AML cell lines-as a warhead. Notably, QP73 significantly induced FTO degradation in a time-, dose-, and ubiquitin-proteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines. Moreover, QP73 treatment significantly increased m⁶A modification on mRNA, promoted myeloid differentiation, and induced apoptosis of AML cells. Quantitative proteomics analysis showed that QP73 induced complete FTO degradation, upregulating RARA and ASB2 abundance and downregulating CEBPA, MYC, PFKP, and LDHB levels in AML cells. Lastly, QP73 exhibited antileukemic activity by increasing m⁶A modification and decreasing FTO levels in xenograft AML tumors. This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications.