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Design of PKC-Targeting Benzolactams as Gli Inhibitors
Marianna Haddad1, Jo Chvatal1, Alexandria Kifer1
1Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, Illinois 60660, United States.
ACS Medicinal Chemistry Letters
|July 14, 2026
Summary
Researchers developed novel benzolactam analogues to inhibit Gli transcription factors, offering a new strategy for cancers resistant to current Hedgehog pathway inhibitors by targeting protein kinase C (PKC).
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Dysregulated Hedgehog signaling, driven by oncogenic Gli transcription factors, is implicated in numerous cancers.
- Resistance to existing Hedgehog pathway inhibitors necessitates Smoothened-independent inhibition strategies.
- Protein kinase C (PKC) mediated inhibition of Gli offers a potential therapeutic avenue.
Purpose of the Study:
- To synthesize and analyze benzolactam analogues as novel Gli inhibitors.
- To investigate structure-activity relationships for PKC-mediated Gli inhibition.
- To provide a framework for developing therapeutics against Gli-driven diseases.
Main Methods:
- Synthesis of benzolactam analogues based on TPPB.
- Structure-activity relationship analysis using Gli-reporter cell-based assays.
- Computational modeling to elucidate drug-target interactions.
Main Results:
- Identification of key structural features for effective Gli inhibition via PKC.
- Benzolactam analogues demonstrated nanomolar potency.
- Novel interactions between benzolactam analogues and the PKC C1 domain were revealed.
Conclusions:
- The developed benzolactam analogues are potent inhibitors of Gli signaling through a PKC-dependent mechanism.
- These findings offer a promising strategy for overcoming resistance to current Hedgehog pathway inhibitors.
- The study provides a foundation for designing novel therapeutics for Gli-driven cancers.
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