Synthesis and mechanistic insights of carbazole-based inhibitors targeting FTO by spectroscopic characterization and molecular simulation.

FTO (Fat mass and obesity-associated protein) is an RNA demethylase crucial for epitranscriptomic regulation, catalyzing the removal of N6-methyladenosine (m6A) modifications. We designed a series of carbazole derivatives and identified compound K27 as a promising FTO inhibitor, exhibiting an IC50 value of 35.58 ± 5.23 μM. Spectroscopic analyses confirmed the binding of K27 to FTO and revealed ligand-induced changes in the protein microenvironment. Moreover, molecular docking and 300 ns molecular dynamics simulations demonstrated stable binding of K27 within the FTO active site. Collectively, these results highlight K27 as a promising lead scaffold for developing FTO inhibitors.