alpha-Aminophosphonates as Potential PARP1 Inhibitors

ADP-ribosyl transferase member 1 (PARP1) is primarily known for its involvement in signaling DNA damage repair mechanisms within a cell. PARP1 inhibitors are used currently for the management of breast cancer (BRCA) gene mutated breast and ovarian cancers. These current generation PARP1 inhibitors are non-selective for PARP1, over the PARP superfamily enzymes. Here we report on a novel class of PARP1 inhibitors, the alpha-aminophosphonates. alpha-Alpha minophosphonates 1-23 were screened in silico for their binding interactions and tested for inhibitory activity against PARP1. alpha-Aminophosphonates 17 and 20 were identified as the most effective PARP1 inhibitors. They inhibited PARP1's activity, at 10 mu M, by 63 +/- 3% and 56 +/- 3%, respectively.