Novel Inhibitors of PARP1/2: A Promising Treatment Approach for BRCA-Negative Cancers, Vascular Disease, and Neurodegeneration

Background

Poly-(ADP-ribose) polymerases 1 and 2 (PARP1/2) function as first responders to DNA damage. Inhibitors of PARP (PARPi) are in clinical use for BRCA-negative breast and ovarian cancer therapy. The use of PARPi leads to synthetic lethality, as the combined loss of BRCA-initiated homologous recombination and PARP1-mediated DNA repair causes death of the cancer cells. PARPi are also being tested as treatment for ischemia-repair injury, vascular disease, and neurodegeneration. PARPi can preserve cardiac cells and neurons by blocking the catalytic activity of PARP1, preventing NAD+ depletion and eventual cell death via necrosis or parthanatos. However, current PARPi do not interact with the previously unknown part of the PARP active site, histone PARylation factor 1 (HPF1).

Technology

The researchers of the University of Colorado Boulder developed a series of novel PARPi compounds which interact with PARP1/2 and HPF1 to form ternary PARP-HPF1 inhibitor complexes. These novel PARPi compounds are configured to interact with HPF1 to form more stable and effective inhibitors. The novel PARPi can inhibit PARP activity, HPF1 activity, and the activity of the PARP-HPF1 complex. The novel PARPi can be therapeutically administered to treat cancers deficient in homologous dependent DNA double strand break repair pathways, vascular disease, as well as cerebral and cardiovascular neurotoxicity.

Advantages

• More stable and effective inhibitors
• Interacts with the HPF1 part of the PARP active site
• Can inhibit PARP activity, HPF1 activity, and the activity of the PARP-HPF1 complex

Applications

• Therapy for cancers deficient in homologous dependent DNA double strand break repair pathways
• Treatment for neurodegenerative and vascular diseases

What's Next?

This technology is available for exclusive partnering or licensing.