Potent and isoform-selective PARP1 degraders for the treatment of BRCA-deficient cancers.

Abstract

PARP inhibitors leverage synthetic lethality in BRCA-mutant tumors, but resistance and PARP2- associated hematological toxicities limit their clinical utility. In this study, a series of novel PROTAC degraders utilizing the highly selective PARP1 inhibitor AZD5305 as the recruiting moiety was reported. Through linker optimization, CPP-13, a pomalidomide-based degrader with a 13-atom linker, was confirmed as the lead compound. CPP-13 exhibited potent PARP1 degradation potency (DC₅₀ = 0.48 nM, D_max = 90%) and robust antiproliferative activity (IC₅₀ = 3.0 nM) in BRCA-deficient cells. Mechanistic investigations confirmed that CPP-13 functions through a CRBN-dependent ubiquitin-proteasome pathway, maintaining high isoform selectivity for PARP1 over PARP2. Furthermore, CPP-13 treatment was associated with γH2AX accumulation and selective growth inhibition in BRCA-deficient breast and pancreatic cancer models. Overall, CPP-13 serves as a valuable chemical tool and demonstrates the feasibility of selective PARP1 degradation using an AZD5305-based PROTAC strategy. Further optimization will be required to improve its pharmacokinetic properties and enable in vivo efficacy evaluation.