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

The fat mass and obesity-associated protein (FTO) is an RNA N 6 -methyladenosine (m 6 A) 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 m 6 A 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.