Tsakoumagkos Ioannis A, Pasquer Quentin T L, Guillod Christian-Louis, Rossion Charlotte, Bagka Meropi, Torche Sonya, Sakata-Kato Tomoyo, Chen James K, Hoogendoorn Sascha
Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland.
Department of Chemical and Systems Biology, Stanford University, 269 Campus Dr., CCSR 3155, Stanford, CA, 94305, USA.
ChemistryOpen. 2025 May;14(5):e202500119. doi: 10.1002/open.202500119. Epub 2025 Apr 14.
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.
对刺猬（HH）信号通路进行表观遗传靶向已成为对抗HH通路驱动癌症的一种可能策略。在本研究中，我们报道了苯并[cd]吲哚-2(1H)-酮作为下游刺猬通路抑制剂。我们发现苯并[cd]吲哚-2(1H)-酮1在多种刺猬通路细胞模型中具有亚微摩尔效力，包括那些因融合抑制因子缺失而具有组成性活性的模型。此外，化合物1降低细胞和纤毛中的GLI水平，并且与BET溴结构域抑制剂HPI-1一样，增加BRD2的细胞水平。为了直接评估化合物1在无需合成修饰的情况下结合细胞中BET溴结构域的能力，我们开发了一种针对降解剂HPP-9的竞争测定法，化合物1的作用呈剂量依赖性地与HPP-9竞争。事实上，化合物1降低了GLI驱动的肺癌细胞和髓母细胞瘤球体的活力，其效力与其对HH通路的抑制作用相似。综上所述，我们的研究突出了苯并[cd]吲哚-2(1H)-酮支架对HH通路进行表观遗传靶向的潜力。
