2. Academic Validation
  3. Rational Design of RNA Demethylase FTO Inhibitors with Enhanced Antileukemia Drug-Like Properties

Rational Design of RNA Demethylase FTO Inhibitors with Enhanced Antileukemia Drug-Like Properties

  • J Med Chem. 2023 Jul 27;66(14):9731-9752. doi: 10.1021/acs.jmedchem.3c00543.
Pan Xiao 1 2,  Zongliang Duan 2 3,  Zeyu Liu 2 4,  Liang Chen 2 4,  Deyan Zhang 1 2 4,  Lu Liu 1 2,  Chen Zhou 5,  Jianhua Gan 6,  Ze Dong 1 2,  Cai-Guang Yang 1 2 3 4
Affiliations

Affiliations

  • 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 College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6 School of Life Sciences, Fudan University, Shanghai 200433, China.
PMID: 37418628 DOI: 10.1021/acs.jmedchem.3c00543
Abstract

The fat mass and obesity-associated protein (FTO) is an RNA N6-methyladenosine (m6A) demethylase highly expressed in diverse cancers including acute myeloid leukemia (AML). To improve antileukemia drug-like properties, we have designed 44/ZLD115, a flexible alkaline side-chain-substituted benzoic acid FTO inhibitor derived from FB23. A combination of structure-activity relationship analysis and lipophilic efficiency-guided optimization demonstrates that 44/ZLD115 exhibits better drug-likeness than the previously reported FTO inhibitors, FB23 and 13a/Dac85. Then, 44/ZLD115 shows significant antiproliferative activity in leukemic NB4 and MOLM13 cell lines. Moreover, 44/ZLD115 treatment noticeably increases m6A abundance on the AML cell RNA, upregulates RARA gene expression, and downregulates MYC gene expression in MOLM13 cells, which are consistent with FTO gene knockdown. Lastly, 44/ZLD115 exhibits antileukemic activity in xenograft mice without substantial side effects. This FTO inhibitor demonstrates promising properties that can be further developed for antileukemia applications.

Figures
Products