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 Overview

The researchers of the University of Colorado 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 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.

Figure 1: The active site formed by the HPF1- PARP1/2 in with a traditional PARPi (Olaparib) that does not interact with HPF1

Figure 2: Chemical structure of a novel PARPi

Benefits

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

Opportunity

Available for exclusive licensing.

CU5352B

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

Patents

IP Status

Seeking