Small molecule protein assembly modulators with pan-cancer therapeutic efficacy

Area of Science:

• Oncology
• Virology
• Pharmacology

Background:

• Two small molecule chemotypes, PAV-617 and PAV-951, demonstrated antiviral activity against Mpox virus and human immunodeficiency virus (HIV), respectively.
• These compounds possess structurally unrelated chemical scaffolds.

Purpose of the Study:

• To investigate the anti-cancer efficacy of PAV-617 and PAV-951.
• To evaluate the safety and therapeutic potential of these compounds as novel cancer treatments.

Main Methods:

• Assessed pan-cancer cytotoxicity in various cancer cell lines.
• Evaluated pharmacokinetics and non-toxicity in cell lines and murine models.
• Validated anti-tumour properties using A549 lung and HT-29 colorectal cancer xenografts in mice.
• Investigated compound interaction with novel, transient, energy-dependent multi-protein complexes.

Main Results:

• Both compounds exhibited apparent pan-cancer cytotoxicity with favorable pharmacokinetics.
• Demonstrated non-toxicity in non-cancer cell lines and in mice at effective concentrations.
• Confirmed anti-tumour activity in mouse xenograft models for lung and colorectal cancers.
• Identified unconventional targets: specific transient multi-protein complexes crucial for cancer survival.

Conclusions:

• PAV-617 and PAV-951 exhibit promising non-toxic, pan-cancer activity by modulating protein complexes that link proliferation and apoptosis.
• These compounds represent potential starting points for developing next-generation, broad-spectrum cancer therapeutics.