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

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

  • ChemistryOpen. 2025 May;14(5):e202500119. doi: 10.1002/open.202500119.
Ioannis A Tsakoumagkos 1,  Quentin T L Pasquer 1,  Christian-Louis Guillod 1,  Charlotte Rossion 1,  Meropi Bagka 1,  Sonya Torche 1,  Tomoyo Sakata-Kato 2 3,  James K Chen 2 4 5,  Sascha Hoogendoorn 1
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland.
  • 2 Department of Chemical and Systems Biology, Stanford University, 269 Campus Dr., CCSR 3155, Stanford, CA, 94305, USA.
  • 3 Present address: Department of Protozoology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
  • 4 Department of Developmental Biology, Stanford University, 269 Campus Dr., CCSR 3155, Stanford, CA, 94305, USA.
  • 5 Department of Chemistry, Stanford University, 269 Campus Dr., CCSR 3155, Stanford, CA, 94305, USA.
PMID: 40227130 DOI: 10.1002/open.202500119
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.

Keywords

BET bromodomains; Hedgehog pathway inhibitor; mechanism-of-action studies; photoaffinity labeling; target identification.

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