The fat mass and obesity-associated protein (FTO) is an RNA -methyladenosine (mA) demethylase highly expressed in diverse cancers including acute myeloid leukemia (AML). To improve antileukemia drug-like properties, we have designed /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 /ZLD115 exhibits better drug-likeness than the previously reported FTO inhibitors, FB23 and /Dac85. Then, /ZLD115 shows significant antiproliferative activity in leukemic NB4 and MOLM13 cell lines. Moreover, /ZLD115 treatment noticeably increases mA abundance on the AML cell RNA, upregulates gene expression, and downregulates gene expression in MOLM13 cells, which are consistent with gene knockdown. Lastly, /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.
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