Exploring Structure Activity Relationship of FOSL1/cJUN Inhibitors Towards Therapeutic Development for Head and Neck Squamous Cell Carcinoma

Authors

Sarita Pandit, Virginia Commonwealth University

Original Publication Date

2026

Document Type

Video

Comments

Presented in the Advancements in Targeted Cancer Therapeutics session.

Abstract

Head and neck squamous cell carcinoma (HNSCC) remains a global health challenge, particularly in HPV-negative, advanced-stage cases where metastatic spread to distant organs results in poor overall survival. Current conventional therapies, such as cisplatin and radiation, often fail due to cancer stem cells (CSCs)—a subpopulation of cells that drive tumor recurrence, metastasis, and intrinsic chemoresistance. This presentation identifies FOSL1, a master regulator of cell proliferation and invasion, as a critical therapeutic target because it is upregulated in HNSCC CSCs and correlates with reduced patient survival.

The researcher utilized a deconstruction-reconstruction-elaboration approach starting with T5224, a molecule originally developed for Phase II clinical trials in rheumatoid arthritis. By systematically breaking down and rebuilding the chemical scaffold, the study identified a specific pharmacophore, the benzoisoxazole group, essential for binding to the FOSL1 protein.

Key Research Findings:

• Enhanced Potency: The lead analog, Compound 3, demonstrated a tenfold increase in potency over the parent compound (T5224) and significantly reduced FOSL1 protein expression in a concentration-dependent manner.
• Selectivity: Compound 3 showed high selectivity for cancer cells (SCC1) over normal cell lines (SGF).
• Anti-Metastatic Properties: In vitro scratch assays confirmed that the compound significantly inhibited cell migration and gap closure more effectively than the parent molecule.
• Targeting Stemness: Sphere-formation assays revealed that Compound 3 effectively inhibits the self-renewal capacity of CSCs, thereby addressing the primary cause of tumor recurrence.
• In Vivo Efficacy: Mouse xenograft models showed a significant reduction in tumor volume at half the T5224 dose, with no observed systemic toxicity or change in body weight.

Keywords

Head and Neck Squamous Cell Carcinoma (HNSCC), FOSL1 (FOS-Like Antigen 1), Cancer Stem Cells (CSCs)

Rights

Copyright © 2026 Sarita Pandit. All rights reserved.