Novel small molecules targeting ciliary transport of Smoothened and oncogenic Hedgehog pathway activation

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The Hedgehog (Hh) pathway is frequently activated in cancers.
• Smoothened (Smo) is a G protein-coupled receptor (GPCR) crucial for Hh pathway activation.
• Trafficking of Smo to the primary cilium (PC) is essential for Hh signaling, making it a therapeutic target.
• Mutations in Smo can lead to drug resistance, a significant challenge in cancer treatment.

Purpose of the Study:

• To identify small molecules that inhibit the transport of constitutively active mutant Smo (SmoM2) to the primary cilium.
• To explore potential therapeutic strategies for drug-resistant SmoM2-driven cancers.

Main Methods:

• High-content screening of compounds in preclinical or clinical development.
• Assessing the ability of compounds to prevent SmoM2 transport into the primary cilium.
• Investigating the molecular mechanisms of compound action, including interactions with Gprasp2 and intracellular trafficking pathways.

Main Results:

• Ten small molecules were identified that inhibit SmoM2 ciliary transport and subsequent Hh pathway activation.
• Eight of these compounds directly interfere with the G protein-coupled receptor associated sorting protein 2 (Gprasp2)-SmoM2 complex.
• One compound, an ionotropic receptor antagonist, inhibits intracellular Smo trafficking to the PC.
• The study revealed potential off-target effects of clinically used drugs.

Conclusions:

• Several identified compounds show promise for treating cancers driven by drug-resistant SmoM2 mutations.
• Targeting the Smo-Gprasp2 complex or intracellular trafficking offers a viable strategy against resistant SmoM2-driven cancers.
• The findings highlight the importance of considering drug off-target effects in clinical settings.