Targeting the Hedgehog pathway with novel Gli1 hydrophobic tagging degraders

The Hedgehog/Glioma-associated oncogene (Hh/Gli) signaling pathway plays an essential role in embryonic development and tissue homeostasis. Aberrant regulation of this pathway has been linked to various human malignancies. Gli1, the downstream transcription factor of the Hh pathway, is the ultimate effector of the canonical Hh pathway and has been identified as a common regulator of several tumorigenic pathways prevalent in Hh-independent cancers. Thus Gli1 represents a unique and promising drug target for a wide range of cancers. However, the identification and development of small molecules that directly target Gli1 protein have progressed slowly, due to an insufficient efficacy and selectivity. Herein, we developed novel small-molecule Gli1 degraders based on the hydrophobic tagging (HyT) strategy. The Gli1 HyT degrader 8e potently inhibited the proliferation of Gli1-overexpressed HT29 colorectal cancer cells, induced Gli1 degradation with a DC50 value of 5.4 & mu;M in HT29 and achieved 70% degradation at 7.5 & mu;M in MEFPTCH1-/- and MEFSUFU-/-cell lines, via proteasome pathway. Compared to the canonical Hh antagonist Vismodegib, 8e exhibited much stronger potency in suppressing the mRNA expression of Hh target genes in Hh-overactivated MEFPTCH1-/- and Vismodegib resistant MEFSUFU-/- cells. Our study provides small molecule Gli1 degraders effectively interfering with both canonical and noncanonical Hh signaling and overcoming current Smoothened (SMO) antagonists resistance, which might pave a new avenue for developing therapeutic modalities targeting Hh/Gli1 signaling pathway.

Automated summary

English Summary: The Hedgehog/Glioma-associated oncogene (Hh/Gli) signaling pathway is crucial for embryonic development and tissue homeostasis, and its dysregulation is associated with various human malignancies. Gli1, a downstream transcription factor of the Hh pathway, is a common regulator of tumorigenic pathways in Hh-independent cancers, making it a promising drug target. However, the development of small molecules that target Gli1 protein has been slow due to lack of efficacy and selectivity. In this study, researchers developed novel Gli1 degraders based on the hydrophobic tagging (HyT) strategy, which effectively inhibited the proliferation of colorectal cancer cells and induced Gli1 degradation. These small molecules showed stronger potency in suppressing Hh target genes compared to the canonical Hh antagonist Vismodegib, and they overcame resistance to current Smoothened (SMO) antagonists. This study provides a new avenue for developing therapeutic approaches targeting the Hh/Gli1 signaling pathway.