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

Article Article scientifique Article Evaluation of Benzo[cd]indol‐2(1H)‐ones as Downstream Hedgehog Pathway Inhibitors eng 2025-04-14 2025-05 author Tsakoumagkos Ioannis 0000-0002-2366-6003 Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland. 936126 author Pasquer Quentin Titouan Loïc 0000-0001-9355-1271 Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland. 943942 Chimie organique (groupe 8) (CHOR8) author Guillod Christian-Louis Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland. 841220 author Rossion Charlotte 0000-0001-9413-754X Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland. 931419 author Bagka Meropi 0009-0006-1733-1641 Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland. 931672 author Torche-Haldimann Sonya Erika Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland. 111610 author Sakata-Kato Tomoyo 0000-0002-8089-5101 Department of Chemical and Systems Biology, Stanford University, 269 Campus Dr., CCSR 3155, Stanford, CA, 94305, USA.,Present address: Department of Protozoology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. author Chen James K 0000-0002-9220-8436 Department of Chemical and Systems Biology, Stanford University, 269 Campus Dr., CCSR 3155, Stanford, CA, 94305, USA.,Department of Developmental Biology, Stanford University, 269 Campus Dr., CCSR 3155, Stanford, CA, 94305, USA.,Department of Chemistry, Stanford University, 269 Campus Dr., CCSR 3155, Stanford, CA, 94305, USA. author Hoogendoorn Sascha 0000-0002-1155-8697 Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland. 917221 Département de chimie organique (CHIOR) e202500119 10.1002/open.202500119 40227130 2191-1363 PMC12075100 https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/open.202500119 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. BET bromodomains Hedgehog pathway inhibitor Mechanism-of-action studies Photoaffinity labeling Target identification Dewey 540 National Institutes of Health R01 CA136574 NIH HHS R03 MH094195 National Research Programme 'NCCR Chemical Biology' Swiss National Science Foundation Inhibitors of cilia and Hedgehog signaling: from phenotype to mechanistic understanding 189246 CH Projects 36 Département de chimie organique 141 false 1380 Groupe Hoogendoorn ChemistryOpen 14 5 3adc3d7e-a23c-428a-a411-9a8e4437a9de Article (Published version) Public ChemistryOpen_-_2025_-_Tsakoumagkos.pdf 2709682 application/pdf CC BY-4.0 559e71172fca314a107426e10acef47b9b472fc0db9db228e77038f477b3d86f openAccess Faculté des sciences / Section de chimie et biochimie / Département de chimie organique

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Evaluation of Benzo[cd]indol‐2(1H)‐ones as Downstream Hedgehog Pathway Inhibitors	ChemistryOpen			2025	33	35

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Guillod, Christian-Louis