%0 Journal Article
%T Allosteric regulation of DNA binding and target residence time drive the cytotoxicity of phthalazinone-based PARP-1 inhibitors.
%A Arnold MR
%A Langelier MF
%A Gartrell J
%A Kirby IT
%A Sanderson DJ
%A Bejan DS
%A Šileikytė J
%A Sundalam SK
%A Nagarajan S
%A Marimuthu P
%A Duell AK
%A Shelat AA
%A Pascal JM
%A Cohen MS
%J Cell Chem Biol
%V 29
%N 12
%D 12 2022 15
%M 36493759
%F 9.039
%R 10.1016/j.chembiol.2022.11.006
%X 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.