Abstract 6172: Characterization of a novel series of highly selective PARP1 inhibitors
Authors: Cowley Phillip M. , McGuinness Barry E. , Campbell Gillian M. , Wise Alan 
Published: April 2023

Abstract
First-generation PARP1 inhibitors have provided significant therapeutic benefit to patients whose tumors exhibit homologous repair deficiencies, including BRCA mutations, however their use has been associated with hematological toxicities that have restricted their application, particularly in combination with standard-of-care chemotherapy. All four FDA-approved PARP1 inhibitors are largely non-selective for the closely related enzyme PARP2, inhibition of which has been shown to drive hematotoxicity. Hence, the development of second-generation molecules highly selective for PARP1 over PARP2 offers a significant opportunity to 1) dramatically enhance therapeutic index, 2) enable additional precision medicine/combination approaches with chemotherapy, radiotherapy, immunotherapy and targeted agents and 3) expand the addressable patient population to those whose tumors harbor additional DDR defects. Utilizing X-ray crystallography and structure-based drug design, we describe the characterization of a novel chemical series of highly selective PARP1 inhibitors. These molecules demonstrate high potency in multiple biochemical and cell-based assays, including viability and colony forming unit read-outs in BRCA-deficient cancer cells, whilst sparing isogenically-paired BRCA wild-type cells and non-transformed primary cell lines. The molecules are potent PARP1-DNA trappers and exhibit high affinity, high selectivity and prolonged residence time in biophysical surface plasmon resonance (SPR) binding assays. The molecules also demonstrate exceptionally high selectivity for PARP1 over PARP2, and across the mono and polyPARP family, using a cell-based NanoBRET target engagement assay. This chemical series generally exhibits highly desirable physico-chemical and in vitro ADME properties, coupled with an excellent in vitro safety profile, which translate to high oral bioavailability and low clearance in rodent PK studies. Lead molecules yield deep and durable anti-tumor efficacy in a BRCA1m MDA-MB-436 breast cancer xenograft model with responses continuing after cessation of treatment. Percent tumor regression and post-dose tumor control was superior to olaparib at 1/10th of the dose. Importantly, our molecules demonstrate prolonged tumor residence time and a markedly superior tumor:plasma ratio compared to competitor PARP1-selective inhibitors. Taken together, these data predict low therapeutic dosing with the potential to demonstrate improved efficacy and tolerability compared to marketed PARP inhibitors. In summary, we describe the characterization of novel potent and selective PARP1 inhibitors. These molecules demonstrate excellent in vitro ADMET and in vivo PK, coupled with profound anti-tumor efficacy and tumor-targeting properties in a genetically-defined mouse model, supporting their progression into clinical studies.
Citation Format: Phillip M. Cowley, Barry E. McGuinness, Gillian M. Campbell, Alan Wise. Characterization of a novel series of highly selective PARP1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6172.