Allosteric regulation of DNA binding and target residence time drive the cytotoxicity of phthalazinone-based PARP-1 inhibitors

Moriah R. Arnold, Marie France Langelier, Jessica Gartrell, Ilsa T. Kirby, Daniel J. Sanderson, Daniel S. Bejan, Justina Šileikytė, Sunil K. Sundalam, Shanthi Nagarajan, Parthiban Marimuthu, Anna K. Duell, Anang A. Shelat, John M. Pascal, Michael S. Cohen*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1694-1708.e10
JournalCell Chemical Biology
Volume29
Issue number12
DOIs
Publication statusPublished - 15 Dec 2022
MoE publication typeA1 Journal article-refereed

Keywords

  • ADP-ribosylation
  • allosteric regulation
  • NAD-competitive inhibitors
  • PARPs
  • target residence time

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