A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N⁶-methyladenosine demethylase FTO.

ABSTRACT: The AlkB family of nucleic acid demethylases are of intense biological and medical interest because of their roles in nucleic acid repair and epigenetic modification. However their functional and molecular mechanisms are unclear, hence, there is strong interest in developing selective inhibitors for them. Here we report the identification of key residues within the nucleotide-binding sites of the AlkB subfamilies that likely determine their substrate specificity. We further provide proof of principle that a strategy exploiting these inherent structural differences can enable selective and potent inhibition of the AlkB subfamilies. This is demonstrated by the first report of a subfamily-selective and cell-active FTO inhibitor 12. The distinct selectivity of 12 for FTO against

SUBMITTER: Toh JDW 

PROVIDER: S-EPMC5424463 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature