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A synthetic combinatorial approach to disabling deviant Hedgehog signaling

C-W Fan1, N Yarravarapu1, H Shi2

  • 1Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

Scientific Reports
|January 20, 2018
PubMed

Insights

A novel dual-action drug (IHR-SAHA) inhibits both Smoothened (SMO) and histone deacetylase (HDAC) pathways. This approach targets cancer drivers and resistance mechanisms in basal cell carcinoma and medulloblastoma.

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.

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