Uncoupling of PARP1 trapping and inhibition using selective PARP1 degradation

Abstract

PARP1 inhibitors (PARPi) are known to kill tumor cells via two mechanisms (i.e., PARP1 catalytic inhibition vs. PARP1 trapping). The relative contribution of these two pathways in mediating the cytotoxicity of PARPi, however, is incompletely understood. Here we designed a series of small molecule PARP degraders. Treatment with one such compound iRucaparib results in highly efficient and specific PARP1 degradation. iRucaparib blocks the enzymatic activity of PARP1 in vitro, and PARP1-mediated PARylation signaling in intact cells. This strategy mimics PARP1 genetic depletion, which enables the pharmacological decoupling of PARP1 inhibition from PARP1 trapping. Finally, by depleting PARP1, iRucaparib protects muscle cells and primary cardiomyocytes from DNA damage-induced energy crisis and cell death. In summary, these compounds represent "non-trapping" PARP1 degraders that block both the catalytic activity and scaffolding effects of PARP1, providing an ideal approach for the amelioration of the various pathological conditions caused by PARP1 hyperactivation.

Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets

“…Pommier et al (2016) systematically reviewed the mechanism of PARP trapping and its relationship with chemoresistance in clinical, provided the implication of PARP trapping for chemotherapy combination. To better understand the two pathways in mediating the cytotoxicity of PARP inhibitors, Wang et al (2019) designed and constructed a series of small molecule PARP degraders to mimic PARP1 genetic depletion and decouple PARP1 catalytic inhibition from PARP1 trapping, showing promising approaches to suppress PARP1 hyperactivation in various pathological conditions. Based on the mechanisms for inhibition of PARP catalytic activities and PARP trapping, several PARP inhibitors (PARPi), such as Olaparib (KuDOS/AstraZeneca) (Mateo et al, 2015), Veliparib (Abbvie) (Kummar et al, 2012), Rucaparib (Pfizer/Clovis) (Swisher et al, 2017), and Niraparib (Merck/Tesaro) (Scott, 2017) have been developed and applied in clinical studies.…”

Small molecules that target the ubiquitin system

“…Whilst selective inhibition of the activity of specific E3 ligases could prove to be of significant therapeutic value, a potentially revolutionary innovation currently gaining widespread attention takes an entirely different approach. Rather than inhibiting E3 ligases, targeted protein degradation, including proteolysis targeting chimeras (PROTACs) [73], immunomodulatory drugs (IMiDs) [74], and specific and nongenetic IAP-dependent protein erasers (SNIPER) [75,76], harnesses the destructive power of the host cell ubiquitin machinery to eliminate unwanted disease-causing proteins in a targeted manner. Since a detailed account, this technology is beyond the scope of this review, we refer readers to many recent reviews that comprehensively summarize recent progress in this field [77][78][79][80][81][82][83][84].…”

PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response

“…Thermo Fisher: Alexa Fluor 488-conjugated goat anti-rabbit IgG (Cat# A32731). The following reagents were used: Talazoparib, Niraparib, Rucaparib, Olaparib, and Veliparib were all purchased from Selleck; iRucaparib-AP6 was synthesized in previous our report (Wang et al, 2019). Dimethyl sulfoxide (DMS), and Lipofectamine 2000 were all purchased from Thermo Fisher Scientific; Polybrene (Hexadimethrine bromide) and Puromycin were purchased from MilliporeSigma.…”