Drug Design and Synthesis of First in Class PDZ1 Targeting NHERF1 Inhibitors as Anticancer Agents

Area of Science:

• Molecular Biology
• Oncology
• Drug Discovery

Background:

• The Sodium-Hydrogen Exchanger Regulatory Factor 1 (NHERF1) is a versatile protein involved in various cellular functions.
• Modulating NHERF1 activity, specifically its PDZ1 domain, is a potential therapeutic strategy, particularly in cancer.
• Current Wnt/β-catenin-targeted therapies face resistance in some colorectal cancer cells.

Purpose of the Study:

• To design and synthesize novel inhibitors targeting the NHERF1 PDZ1 domain.
• To explore the therapeutic potential of these inhibitors in combination with β-catenin antagonists.
• To augment apoptotic cell death in colorectal cancer cells refractory to existing treatments.

Main Methods:

• Design and chemical synthesis of specific NHERF1 PDZ1 domain inhibitors.
• Evaluation of inhibitor efficacy in preclinical cancer models.
• Combination therapy studies with Wnt/β-catenin pathway antagonists.

Main Results:

• Successful design and synthesis of novel NHERF1 PDZ1 domain inhibitors.
• Demonstrated potential for these compounds to enhance apoptosis in colorectal cancer cells.
• Synergistic effect observed when combined with β-catenin antagonists in resistant cancer cells.

Conclusions:

• Targeted inhibition of the NHERF1 PDZ1 domain offers a promising therapeutic avenue.
• Novel NHERF1 inhibitors show potential for overcoming resistance to Wnt/β-catenin therapies.
• Combination strategies involving NHERF1 inhibitors could improve outcomes for refractory colorectal cancers.