Rational Design and Optimization of m⁶A-RNA Demethylase FTO Inhibitors as Anticancer Agents.

ABSTRACT: Aberrant regulation of N⁶-methyladenosine (m⁶A) RNA modification has been implicated in the progression of multiple diseases, including cancer. Previously, we identified a small molecule inhibitor of the m⁶A demethylase fat mass- and obesity-associated protein (FTO), which removes both m⁶A and N⁶,2'-O-dimethyladenosine (m⁶A_m) RNA modifications. In this work, we describe the rational design and optimization of a new class of FTO inhibitors derived from our previous lead FTO-04 with nanomolar potency and high selectivity against the homologous m⁶A RNA demethylase ALKBH5. The oxetanyl class of compounds comprise competitive inhibitors of FTO with potent antiproliferative effects in gli

SUBMITTER: Huff S 

PROVIDER: S-EPMC9421652 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature