{Reference Type}: Journal Article
{Title}: Allosteric regulation of DNA binding and target residence time drive the cytotoxicity of phthalazinone-based PARP-1 inhibitors.
{Author}: Arnold MR;Langelier MF;Gartrell J;Kirby IT;Sanderson DJ;Bejan DS;Šileikytė J;Sundalam SK;Nagarajan S;Marimuthu P;Duell AK;Shelat AA;Pascal JM;Cohen MS;
{Journal}: Cell Chem Biol
{Volume}: 29
{Issue}: 12
{Year}: 12 2022 15
{Factor}: 9.039
{DOI}: 10.1016/j.chembiol.2022.11.006
{Abstract}: Allosteric coupling between the DNA binding site to the NAD+-binding pocket drives PARP-1 activation. This allosteric communication occurs in the reverse direction such that NAD+ mimetics can enhance PARP-1's affinity for DNA, referred to as type I inhibition. The cellular effects of type I inhibition are unknown, largely because of the lack of potent, membrane-permeable type I inhibitors. Here we identify the phthalazinone inhibitor AZ0108 as a type I inhibitor. Unlike the structurally related inhibitor olaparib, AZ0108 induces replication stress in tumorigenic cells. Synthesis of analogs of AZ0108 revealed features of AZ0108 that are required for type I inhibition. One analog, Pip6, showed similar type I inhibition of PARP-1 but was ∼90-fold more cytotoxic than AZ0108. Washout experiments suggest that the enhanced cytotoxicity of Pip6 compared with AZ0108 is due to prolonged target residence time on PARP-1. Pip6 represents a new class of PARP-1 inhibitors that may have unique anticancer properties.