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 outcompeted by compound 1. Indeed, compound 1 reduces the viability of GLI-driven lung cancer cells and medulloblastoma spheroids, with a potency similar to its inhibitory effect on the HH pathway. Taken together, our studies highlight the potential of the benzo[cd]indol-2(1H)-one scaffold for epigenetic targeting of the HH pathway.