DNA double-strand breaks (DSBs), the most lethal DNA lesions, are usually repaired by BRCA1/2-mediated homologous recombination (BRCA-HR) and DNA-PK-mediated non-homologous end-joining (D-NHEJ) in proliferating cells . Poly [ADP-ribose] polymerase 1 (PARP1) may prevent accumulation of potentially lethal DNA double-strand breaks (DSBs) by playing a key role in base excision repair (BER), single-strand break (SSB) repair, alternative non-homologous end-joining (Alt-NHEJ), and by facilitating MRE11-mediated recruitment of RAD51 to promote stalled replication fork restart . The success of the PARP inhibitor (PARPi) olaparib in BRCA1/2-deficient breast tumors has established a proof-of-concept of personalized cancer therapy utilizing synthetic lethality. Unfortunately, the therapeutic effect of PARPi is usually short-lived as tumor cells become unresponsive due to a variety of compensatory mechanisms. In order to address this issue, we have focused our efforts on developing novel allosteric PARPi’s that target a non-nicotinamide adenine dinucleotide (NAD) binding site on PARP1. These novel compounds could be employed in combination with known PARPi’s that target NAD to decrease the likelihood of cancer resistance.
Moulder Center for Drug Discovery Research
Temple University School of Pharmacy
3307 N Broad Street
Philadelphia, PA 19140