Allosteric regulation of DNA binding and target residence time drive the cytotoxicity of phthalazinone-based PARP-1 inhibitors.
Cell Chem Biol
; 29(12): 1694-1708.e10, 2022 12 15.
Article
in En
| MEDLINE
| ID: mdl-36493759
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 â¼90-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Poly(ADP-ribose) Polymerase Inhibitors
/
Antineoplastic Agents
Language:
En
Journal:
Cell Chem Biol
Year:
2022
Type:
Article
Affiliation country:
United States