Antitumor Efficacy of 1,2,4-Triazole-Based VCP/p97 Allosteric Inhibitors

Area of Science:

• Biochemistry and Molecular Biology
• Cancer Research and Therapeutics
• Drug Discovery and Development

Background:

• The AAA ATPase p97 (VCP) is vital for protein homeostasis and the ubiquitin-proteasome system.
• Cancer cells exhibit high mutational loads and protein quality control defects, making p97 a promising therapeutic target.

Purpose of the Study:

• To optimize the 3-thioalkyl-1,2,4-triazol-pyridyl allosteric inhibitor scaffold for p97 (VCP).
• To identify novel p97 (VCP) inhibitors with potent biochemical and cellular activity.
• To evaluate the in vivo efficacy and resistance profile of optimized compounds.

Main Methods:

• Chemical optimization of a known allosteric inhibitor scaffold.
• Biochemical and cellular assays to determine inhibitor potency.
• In vivo studies using mouse xenograft models to assess antitumor efficacy and biomarker modulation.
• Evaluation of compound activity against VCP ATP-site mutants and resistant cell lines.

Main Results:

• Two optimized compounds, 25 and 38, achieved low-nanomolar biochemical potency and submicromolar cellular inhibition.
• Compounds demonstrated in vivo effects on VCP inhibition biomarkers and significant antitumor efficacy in xenograft models.
• Compound 38 effectively inhibited VCP ATP-site mutants and the growth of cells resistant to CB-5083.

Conclusions:

• The optimized allosteric inhibitors, particularly compound 38, represent promising novel therapeutics for cancer.
• These compounds show potential for overcoming resistance mechanisms associated with existing VCP inhibitors.
• Further development of these p97 (VCP) inhibitors warrants investigation for clinical application in oncology.