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

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

doi:10.1016/j.chembiol.2022.11.006

Cited by 5 publications

(3 citation statements)

References 33 publications

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“…We have shown recently that reverse allostery can play a role in modulating the ability of a PARPi to kill cancer cells by converting a type III PARPi (veliparib) into a type I inhibitor (UKTT15) of PARP1 ( 35 ). Moreover, a recent study introduced structural alterations that converted olaparib from a type II inhibitor of PARP1 to a type I inhibitor that exhibited greater cell killing ( 45 ). However, inhibitory potency and binding kinetics also play a critical role in determining the overall efficiency of a PARPi ( 33 , 34 , 45 ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a recent study introduced structural alterations that converted olaparib from a type II inhibitor of PARP1 to a type I inhibitor that exhibited greater cell killing ( 45 ). However, inhibitory potency and binding kinetics also play a critical role in determining the overall efficiency of a PARPi ( 33 , 34 , 45 ). Since none of the current clinical PARPi have a proretention reverse allosteric effect on PARP1, it would be interesting to design and study novel PARPi that feature this characteristic for PARP1 but that do not target PARP2.…”

Section: Discussionmentioning

confidence: 99%

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Clinical PARP inhibitors allosterically induce PARP2 retention on DNA

et al. 2023

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PARP1 and PARP2 detect DNA breaks, which activates their catalytic production of poly(ADP-ribose) that recruits repair factors and contributes to PARP1/2 release from DNA. PARP inhibitors (PARPi) are used in cancer treatment and target PARP1/2 catalytic activity, interfering with repair and increasing PARP1/2 persistence on DNA damage. In addition, certain PARPi exert allosteric effects that increase PARP1 retention on DNA. However, no clinical PARPi exhibit this allosteric behavior toward PARP1. In contrast, we show that certain clinical PARPi exhibit an allosteric effect that retains PARP2 on DNA breaks in a manner that depends on communication between the catalytic and DNA binding regions. Using a PARP2 mutant that mimics an allosteric inhibitor effect, we observed increased PARP2 retention at cellular damage sites. The PARPi AZD5305 also exhibited a clear reverse allosteric effect on PARP2. Our results can help explain the toxicity of clinical PARPi and suggest ways to improve PARPi moving forward.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical PARP inhibitors allosterically induce PARP2 retention on DNA

et al. 2023

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“… 66 In PARP1, such an effect has so far been reported only with nonclinical inhibitors. 66 , 179 In PARP2, more inhibitors, including clinically relevant PARPi, have been shown to lead to allosterically induced stalling due to subtle structural differences from PARP1. 180 , 181 …”

Section: Adp-ribosylation In Human Disease and Therapymentioning

confidence: 99%