Discovery of novel pentacyclic indolocyclopentaphthalazinone PARP1 inhibitors

The National Institute of General Medical Sciences awarded St. John's University, New York, $150,000 on August 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to discover and develop novel pentacyclic indolocyclopentaphthalazinone PARP1 inhibitors for cancer treatment.

The research addresses limitations of existing PARP inhibitors, which potently inhibit both PARP1 and PARP2 enzymes and exhibit variable clinical efficacy compromised by dose-limiting toxicities and acquired drug resistance. The project aims to develop a novel class of highly selective PARP1 inhibitors that exhibit moderate PARP1 trapping potency while evading ABC transporter-mediated efflux. The work builds on a published discovery from the recipient's laboratory featuring lead compound 5, which demonstrates single-digit nanomolar potency against PARP1 with greater than 25-fold selectivity over PARP2 and other PARP enzymes. Lead compound 5 shows substantially lower PARP1 trapping compared to talazoparib and favorable oral bioavailability with desirable Caco-2 permeability and efflux ratios, potentially enabling application to brain tumors and combination therapies while mitigating hematologic toxicity.

Performance occurs in Jamaica, New York. The period of performance runs from August 1, 2026, through April 30, 2030.

Abstract

The use of parp inhibitors (parpi) has revolutionized the treatment of DNA damage repair defective cancers (brca deficiencies) by synthetic lethality. One of the key challenges with this approach is that existing parpi potently inhibits both PARP1 and PARP2 enzymes. These agents demonstrate marked variability in clinical efficacy, which is often compromised by dose-limiting toxicities due to PARP2 inhibition and trapping, as well as excessive trapping of PARP1. Furthermore, their susceptibility to ATP-binding cassette (ABC) transporter- mediated efflux contributes to acquired drug resistance. Notably, none of the parpi were specifically designed to only block PARP1 in a way that limits harmful trapping effects or to effectively penetrate the blood-brain barrier (BBB). As a result, their clinical use is largely limited to tumors outside the CNS. This proposal seeks to overcome the limitations of current parpi by developing a novel class of highly selective PARP1 inhibitors that exhibit moderate PARP1 trapping potency while evading ABC transporter-mediated efflux. The foundation of this proposal is a key published discovery made in our laboratory. This discovery involves lead compound 5 that features a novel molecular architecture and exhibits single-digit nanomolar potency against PARP1, with >25- fold selectivity over PARP2 and other parps, reducing toxicity risk. Lead 5 showed a substantially lower PARP1 trapping compared to strong PARP1 trapping agent talazoparib, a desirable property that may help mitigate dose-limiting hematologic toxicity in combination therapy and reduce the need for dose adjustments or drug holidays. Desirable caco-2 permeability of 5 (PE = 42 NM/SEC) with efflux ratio (ER) of 0.9 potentially offer favorable oral bioavailability and efficient absorption across epithelial barriers. Compound 5 is not a substrate for key ABC transporters such as p-GP, as evidenced by ER data, thus reducing the risk of efflux-mediated resistance and improving BBB permeability. Compound 5 also showed cellular inhibition of parylation activity comparable to olaparib. With a low molecular weight (277 DA), compound 5 aligns well with drug-like properties, offering advantages in formulation and effective distribution to tumor microenvironment. Our lead compound, being a novel entry in parpi field, provides an opportunity to develop best-in-class therapy. Finally, the optimization of lead 5 introduces novel synthetic strategies that not only enhance its development but also provides a valuable platform for the efficient synthesis of a broader class of related pentacyclic compounds. Aim 1 assays will measure PARP1 potency and selectivity in cell-free systems, assess affinity for other parp homologs, and optimize physicochemical properties for in vitro use. Novel PARP1 selective inhibitors will be evaluated for in vitro safety using non-transformed cell lines, HEK-293 and mdck.1, as well as for their PARP1 inhibitory activity and trapping potency in brca mutant cell lines (aim 1). Aim 2 will assess cytotoxic efficacy of top PARP1 selective inhibitors in brca isogenic 2D and 3D cell culture models.