Candidate PARPi compounds with strong anti-cancer capabilities (i.e. “DNA trappers”) and PARPi candidates with low cellular toxicity for treatment of stroke, diabetes, myocardial infarction, neurodegenerative diseases and other diseases with PARP overactivation (i.e. “non-trappers”).
Inhibition of Poly(ADP‐ribose) polymerase 1 (PARP-1) is a clinically approved approach for the treatment of cancer. While PARP inhibitors (PARPi) can be potent at cancer cell killing, they often suffer from short plasma half-life, resistance mechanisms, and off-target effects such as hematologic toxicity. Given the narrow therapeutic window of the existing PARPi, there is a need for improved PARPi to achieve an optimal effect on cancer cells.
Dr. Black and his team have developed a method that allows one to determine whether a PARPi may represent a strong anticancer compound (i.e. a “DNA trapping” compound which “traps” PARP at DNA break sites) or a compound that would be a strong candidate for treatment of other diseases (i.e. a “non-trapping” compound with low cellular toxicity) (19-8790-01).
Using this approach, the inventors have identified that the PARPi Veliparib, which recently failed in Phase III clinical trials for breast and lung cancer, fails to cause ‘allosteric’ trapping of PARP-1 at a DNA break. Based on the analysis of the structural and dynamic changes within the Veliparib-bound PARP-1 enzyme, the team was able to create a subset of Veliparib derivatives with much higher “DNA trapping” and cell killing.
As in many cancer cells, PARP activity is also increased in a number of diseases such as stroke, diabetes, myocardial infarction, and neurodegenerative diseases, where PARP activation contributes to undesired cell death. The inventors continue the development of PARPi with low “DNA trapping” capabilities and reduced cytotoxicity.
PARP inhibitors for the treatment of diseases where PARP activation plays a role - cancer, stroke, diabetes, myocardial infarction, neurodegenerative diseases, and others.