Benzolactam-Based Gli Inhibitors: Synthesis and Structural Analysis

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• The Hedgehog signaling pathway is crucial in cancer, particularly basal cell carcinoma and medulloblastoma.
• Oncogenic Gli transcription factors drive this pathway, regulated by Smoothened (Smo).
• Existing Smo inhibitors face limitations due to drug resistance.

Purpose of the Study:

• To synthesize and evaluate TPPB, a novel benzolactam-derived Gli inhibitor acting downstream of Smo.
• To explore Smo-independent inhibition strategies for overcoming drug resistance.
• To identify structural features of benzolactam derivatives important for Gli inhibition.

Main Methods:

• Developed a concise, stereoselective synthesis for the benzolactam scaffold and TPPB.
• Assessed TPPB's inhibitory activity and mechanism via protein kinase C (PKC) activation.
• Conducted *in vivo* testing in a Gli-dependent basal cell carcinoma model.
• Employed function-oriented synthesis to create simplified analogues.

Main Results:

• Successfully synthesized TPPB using an efficient stereoselective route.
• TPPB demonstrated potent Gli inhibition downstream of Smo, mediated by PKC activation.
• *In vivo* studies confirmed TPPB's antitumor efficacy in a basal cell carcinoma model.
• Identified key benzolactam structural motifs crucial for Gli inhibition.

Conclusions:

• TPPB represents a promising Smo-independent Gli inhibitor for cancer therapy.
• The synthetic route provides access to novel benzolactam-based compounds.
• Findings offer guidelines for designing next-generation Gli inhibitors to overcome resistance.