2. Academic Validation
  3. Structure-Activity Relationships and Antileukemia Effects of the Tricyclic Benzoic Acid FTO Inhibitors

Structure-Activity Relationships and Antileukemia Effects of the Tricyclic Benzoic Acid FTO Inhibitors

  • J Med Chem. 2022 Aug 11;65(15):10638-10654. doi: 10.1021/acs.jmedchem.2c00848.
Zeyu Liu 1 2,  Zongliang Duan 1 3,  Deyan Zhang 4 2,  Pan Xiao 4,  Tao Zhang 1,  Hongjiao Xu 1,  Chuan-Hui Wang 5,  Guo-Wu Rao 5,  Jianhua Gan 6,  Yue Huang 1 4,  Cai-Guang Yang 1 3 4 2,  Ze Dong 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Centre for the Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 5 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China.
  • 6 School of Life Sciences, Fudan University, Shanghai 200433, China.
PMID: 35793358 DOI: 10.1021/acs.jmedchem.2c00848
Abstract

The N6-methyladenosine (m6A) demethylase FTO is overexpressed in acute myeloid leukemia (AML) cells and promotes leukemogenesis. We previously developed tricyclic benzoic acid FB23 as a highly potent FTO inhibitor in vitro. However, it showed a moderate antiproliferative effect on AML cells. In this work, we performed a structure-activity relationship study of tricyclic benzoic acids as FTO inhibitors. The analog 13a exhibited excellent inhibitory effects on FTO similar to that of FB23 in vitro. In contrast to FB23, 13a exerted a strong antiproliferative effect on AML cells. Like FTO knock down, 13a upregulated ASB2 and RARA expression and increased the protein abundance while it downregulated MYC expression and decreased MYC protein abundance. These genes are key FTO targets in AML cells. Finally, 13a treatment improved the survival rate of MONOMAC6-transplanted NSG mice. Collectively, our data suggest that targeting FTO with tricyclic benzoic acid inhibitors may be a potential strategy for treating AML.

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