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 [3]. 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 [4]. 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.