2. Academic Validation
  3. Discovery of Novel RNA Demethylase FTO Inhibitors Featuring an Acylhydrazone Scaffold with Potent Antileukemia Activity

Discovery of Novel RNA Demethylase FTO Inhibitors Featuring an Acylhydrazone Scaffold with Potent Antileukemia Activity

  • J Med Chem. 2025 Feb 13;68(3):2742-2763. doi: 10.1021/acs.jmedchem.4c02076.
Xuewu Liang 1 2,  Yue Huang 1 2 3,  Hairu Ren 1 2 3,  Qi Liu 1 2,  Liang Chen 1 2,  Jiayan Zhao 3,  Xiangqian Gao 1 2,  Jian Lu 3,  Cai-Guang Yang 1 2 3 4,  Hong Liu 1 2 3 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 4 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
  • 5 College of Pharmacy, Xinjiang Medical University, Urumqi 830011, Xinjiang China.
PMID: 39818964 DOI: 10.1021/acs.jmedchem.4c02076
Abstract

Fat mass obesity-associated protein (FTO) has been emerging as a potential therapeutic target for drug discovery in RNA Epigenetics. In this work, a series of novel FTO inhibitors featuring an acylhydrazone scaffold were identified, and the optimized compounds 8t-v showed potent FTO inhibitory activities with IC50 values ranging from 7.1 to 9.4 μM. FTO inhibitor 8t, as the lead compound, exhibited potent antiproliferative capacities against MOLM13, NB4, and THP-1 with IC50 values of 0.35, 0.59, and 0.70 μM, respectively, and remarkably induced NB4 cell Apoptosis. Compound 8t also inhibited the FTO demethylation, enhanced the abundance of m6A, stabilized FTO protein folding, and regulated the oncogenic FTO signaling pathway. Importantly, compound 8t significantly caused a tumor volume reduction and tumor weight loss with a tumor growth inhibition (TGI) value of 51% in NB4 xenograft mice. Overall, our work provided valuable lead compounds for FTO inhibitors featuring an acylhydrazone scaffold with potent antileukemia activity both in vitro and in vivo.

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