Methodology by which to identify candidate PARP inhibitors with strong anti-cancer properties (i.e. “trapping” compounds), as well as PARP inhibitors with low cellular toxicity for treatment of stroke, diabetes, myocardial infarction, neurodegenerative diseases and other diseases (i.e. a “non-trapping” compounds)
Inhibition of Poly(ADP‐ribose) polymerase PARP is a clinically approved approach for the treatment of cancer where PARP inhibitors (PARPi) are used with the goal of robust killing of cancer cells. On the other hand, PARP activity is increased in a number of diseases such as stroke, diabetes, myocardial infarction, and neurodegenerative diseases where PARP activation contributes to undesired cell death. Thus, for the purposes of cancer treatment PARPi need to effectively kill the target cells, while in the other diseases PARPi need to inhibit enzyme activity while keeping target cells alive and healthy. The difference in the effect of PARPi on cells is largely determined by their ability to form PARP-DNA complexes (e.g. “trapping” DNA) which leads to cell killing, while “non-trapping” PARPi’s activity is caused by inhibiting activity of PARP enzymes.
Dr. Black and his team have discovered specific changes in structure and molecular contacts within PARP enzymes caused by PARPi. Using biochemical and biophysical methodologies the team is able to determine whether a candidate PARPi compound may represent a strong anti-cancer compound (i.e. a “trapping” compound that would be a robust cancer cell killer) or a compound that would be a strong candidate for treatment of other diseases (i.e. a “non-trapping” compound with low cellular toxicity). Using this method the team has developed a series of "trapping" and "non-trapping" PARP inhibitors (19-8790
Identification of PARPi candidate compounds for oncology indications or treatment of other diseases with PARP over-activation
Stage of Development:
Validated in a series of existing and novel PARP inhibitors