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

Pan Xiao; Zongliang Duan; Zeyu Liu; Liang Chen; Deyan Zhang; Lu Liu; Chen Zhou; Jianhua Gan; Ze Dong; Cai-Guang Yang

doi:10.1021/acs.jmedchem.3c00543

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. Epub 2023 Jul 7.

Authors

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 Zhou⁵, Jianhua Gan⁶, Ze Dong^{1

2}, Cai-Guang Yang^{1

2

3

4}

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
Animals
Cell Line
Genes, myc
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Mice
RNA*
Structure-Activity Relationship

Substances

RNA
Alpha-Ketoglutarate-Dependent Dioxygenase FTO
FTO protein, human
FTO protein, mouse