A synthetic combinatorial approach to disabling deviant Hedgehog signaling

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Mutations in the Hedgehog (HH) signaling pathway are prevalent in basal cell carcinoma (BCC) and medulloblastoma.
• Cancer cells develop resistance to Smoothened (SMO) antagonists by activating alternative GLI transcription factor pathways.

Purpose of the Study:

• To develop a novel therapeutic agent targeting both SMO and GLI activity.
• To investigate a dual SMO-HDAC antagonist for overcoming drug resistance in cancers driven by HH pathway mutations.

Main Methods:

• Design and synthesis of a small molecule SMO-HDAC antagonist (IHR-SAHA).
• Evaluation of IHR-SAHA's inhibitory activity against SMO-dependent and SMO-independent GLI transcription.
• Assessment of IHR-SAHA's potential in cancer biogenesis and drug resistance models.

Main Results:

• IHR-SAHA effectively inhibits GLI transcription through simultaneous targeting of the SMO heptahelical domain and histone deacetylase (HDAC) enzymes.
• The compound demonstrates efficacy against SMO-dependent and SMO-independent mechanisms of GLI activation.
• IHR-SAHA shows potential as a combinatorial therapeutic agent against cancer drivers and resistance pathways.

Conclusions:

• Dual inhibition of SMO and HDAC pathways represents a promising strategy for treating HH-driven cancers.
• Synthetic combinatorial agents like IHR-SAHA can disable cancer drivers and anticipated resistance mechanisms.
• This approach may prolong disease remission and offers a new clinical development path for combination therapies.