Evaluation of Benzo[cd]indol-2(1H)-ones as Downstream Hedgehog Pathway Inhibitors.

ABSTRACT: Epigenetic targeting of the Hedgehog (HH) signaling pathway has emerged as a possible strategy to combat HH pathway-driven cancers. In this study, we report on benzo[cd]indol-2(1H)-ones as downstream Hedgehog pathway inhibitors. We find that benzo[cd]indol-2(1H)-one 1 has sub-micromolar potency in a variety of Hedgehog pathway cell models, including those with constitutive activity through loss of Suppressor of Fused. Compound 1 furthermore reduces cellular and ciliary GLI levels, and, like the BET bromodomain inhibitor HPI-1, increases the cellular levels of BRD2. To directly assess the ability of compound 1 to bind to BET bromodomains in cells without the need of synthetic modifications, we develop a competition assay against degrader HPP-9, the action of which was dose-dependently outco

SUBMITTER: Tsakoumagkos IA 

PROVIDER: S-EPMC12075100 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature