N'-(1-phenylethylidene)-benzohydrazide cytotoxicity is LSD1 independent and linked to Fe-S cluster disruption in Ewing sarcoma.

ABSTRACT: The noncompetitive LSD1 inhibitors SP-2509 and SP-2577 are N'-(1-phenylethylidene)-benzohydrazides that display potent activity in Ewing sarcoma. They block transcriptional regulation of the causative oncogenic fusion protein, EWSR1::FLI1, and cause cell death. However, SP-2509 and SP-2577 are the only LSD1 inhibitors active in Ewing sarcoma; other LSD1 inhibitors have little effect. Studies from our group and others suggest SP-2509 activity may result from off-target activity affecting the mitochondria. Here we identified potential off-target mechanisms of N'-(1-phenylethylidene)-benzohydrazides using an unbiased approach, cellular thermal shift assay coupled to mass spectrometry (CETSA-MS). Interestingly, this revealed significant destabilization of the electron transport chain complex I

SUBMITTER: Sherman JW 

PROVIDER: S-EPMC12262209 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature