Covalent adduct Grob fragmentation underlies LSD1 demethylase-specific inhibitor mechanism of action and resistance.

ABSTRACT: Chromatin modifiers often work in concert with transcription factors (TFs) and other complex members, where they can serve both enzymatic and scaffolding functions. Due to this, active site inhibitors targeting chromatin modifiers may perturb both enzymatic and nonenzymatic functions. For instance, the antiproliferative effects of active-site inhibitors targeting lysine-specific histone demethylase 1A (LSD1) are driven by disruption of a protein-protein interaction with growth factor independence 1B (GFI1B) rather than inhibition of demethylase activity. Recently, next-generation precision LSD1 covalent inhibitors have been developed, which selectively block LSD1 enzyme activity by forming a compact N-formyl flavin adenine dinucleotide (FAD) adduct that spares the GFI1B interaction. Howeve

SUBMITTER: Waterbury AL 

PROVIDER: S-EPMC11965392 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature