AbstractThe DNA Damage Response (DDR) is an integrated network of DNA repair and cell signaling pathways that are critical towards maintaining genomic stability. The most successful DDR targeted therapies inhibit the DNA damage sensor, PARP, a protein that recognizes single strand DNA (ssDNA) breaks as well as other DNA secondary structures induced by single strand gaps that can initiate chromosome instability and cell death. Building on the initial clinical success of PARP inhibitors, development of DDR targeted therapeutics has become increasingly popular, however, the clinical outcomes with these therapeutics have not met expectations and thus a new approach to targeting the DDR pathway is needed. NERx Biosciences has developed a novel strategy of targeting the DDR by intervening upstream of the DDR kinases and targeting specific DDR sensors. The human ssDNA binding protein, replication protein A (RPA), is a critical sensor for the DDR, serving to sense the ssDNA at replication forks that arise from replication stress (RS) and is a novel target for cancer therapy. We have discovered, developed, and characterized a novel small molecule RPA inhibitor (RPAi) NERx-329 that blocks the RPA-DNA interaction and elicits a state of chemical RPA exhaustion that results in in vivo anticancer activity. Extensive chemical optimization enabled in vitro and in vivo analyses to elucidate mechanism of action, cellular engagement, and therapeutic activity of RPA-targeted agents. Biochemical reconstitution of the ATR signaling pathway shows that NERx-329 disrupts ATR kinase activity, further suggesting a novel mechanism of action driven by RPA inhibition induced replication catastrophe. In vivo analysis reveals activity in a series of lung and ovarian patient derived xenograft models of human cancer. Single agent activity results in a tumor growth delay, which can be enhanced in combination therapy with DDR inhibitors as well as traditional DNA damaging cancer therapeutics. Data demonstrate that tumor growth observed in vivo is a function of NERx329 bioavailability and not development of a specific resistance mechanism. In an effort to identify formulations effective in enhancing oral bioavailability, we have pursued the development of Spray-dried dispersions (SDD). PK analysis reveal a dose-dependent substantial increase in CMAX and AUC, allowing for optimal dosing regimens for efficacy and safety studies. In addition, specific genetic predictors of RPAi sensitivity have been identified and results demonstrate specific genetic alterations increase RPAi activity in vitro and in vivo. NERx-329 represents the first clinically viable agent to target the DDR pathway by disrupting the RPA-DNA interaction and holds the potential for significant impact in cancer treatment.Citation Format: Katherine Pawelczak, Pamela VanderVere-Carozza, Matthew Jordan, John Turchi. Targeting the DNA damage response sensor replication protein A for first in class cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5616.

2023-12-01·Molecular Cancer Therapeutics

Abstract B052: Small molecule RPA inhibitors abrogate the ATR kinase signaling pathway

作者: Jordan, Matthew R ; Turchi, John J ; Gavande, Navnath S ; Ainembabazi, Diana ; Pawelczak, Katherine S ; VanderVere-Carozza, Pamela S

AbstractReplication Protein A (RPA) is the major single-stranded DNA (ssDNA) binding protein in the cell and plays a role in replication, recombination, and the DNA damage response (DDR) and repair. RPA functions to protect ssDNA from degradation and also serves as an interaction hub to recruit replication and DDR machinery. Under normal cellular conditions, RPA protein abundance is in excess to that of the ssDNA generated during S phase replication so as to protect from replication fork collapse and replication catastrophe in the event of elevated levels of replication stress. RPA inhibition is thus a promising cancer therapeutic strategy that targets oncogenic cells with increased replication stress due to rapid cell proliferation, genotoxic stressors, DDR inhibition, etc, and therefore an increased ssDNA burden. We have previously developed the RPA inhibitor (RPAi) NERx329 that disrupts RPA-ssDNA binding and exhibits single agent anti-cancer activity in vitro and in vivo presumably due to chemical RPA exhaustion. When a cell experiences extensive replication stress, elevated levels of RPA-bound ssDNA are recognized by the kinase ataxia telangiectasia and Rad2-related (ATR) through the ATR interacting protein (ATRIP). ATR is then activated through interactions with DNA topoisomerase 2-binding protein 1 (TopBP1) and phosphorylates downstream targets largely to direct the G2/M checkpoint signaling pathway through checkpoint kinase 1 (CHK1). In this work, we biochemically reconstitute this signaling pathway in order to evaluate an RPAi mechanism of action. We utilize a ssDNA substrate that mimics a stalled replication fork and demonstrate the RPA-dependence of ATR activation by monitoring phosphorylation of multiple ATR substrates: RPA, TopBP1, and p53. We then show that RPAi disrupt ATR kinase activity. Collectively, this works describes a novel mechanism of action of RPAi whereby RPA inhibition results in replication catastrophe by blocking the ATR activity and the G2/M checkpoint pathway.Citation Format: Matthew R Jordan, Diana Ainembabazi, Pamela S VanderVere-Carozza, Navnath S Gavande, Katherine S Pawelczak, John J Turchi. Small molecule RPA inhibitors abrogate the ATR kinase signaling pathway [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B052.

2017-07-01·Cancer Research

Abstract 1416: Development of small molecule inhibitors for cancer therapy by targeting RPA and XPA nucleotide excision repair proteins

作者: Turchi, John J. ; Gavande, Navnath S. ; VanderVere-Carozza, Pamela S. ; Vernon, Tyler L. ; Pawelczak, Katherine

AbstractTargeting DNA repair and the DNA damage response for cancer therapy has recently gained increasing attention with inhibitors of the PARP enzyme showing a therapeutic efficacy in various cancers. Solid tumors of the lung, pancreas, breast, and ovary represent a continuing clinical challenge in treatment and together account for over 250,000 deaths in the US alone, representing over 40% of all cancer deaths. There are limited therapeutic options for these patients, and targeted and combination therapies remain necessary for treating these aggressive cancers. The opportunity exists to exploit recent scientific advances in our knowledge of the underlying biology behind these cancers to create novel targeted therapeutics to dramatically enhance patient response to therapy and ultimately survival. To this end, we have developed a series of novel small chemical molecules that disrupt critical protein-DNA interactions in the nucleotide excision repair (NER) pathways. It is well understood that various cancer treatments like cisplatin, etoposide and ionizing radiation impart their chemotherapeutic effect by the formation of direct DNA damage which block DNA replication and transcription culminating in apoptosis. It is also well established that repair of this DNA damage by nucleotide excision repair (NER) or homologous recombination repair (HRR) reduces the effectiveness of chemo- or radio- therapy. Replication protein A (RPA) and Xeroderma Pigmentosum Group A (XPA) plays a crucial role in the NER pathway and makes them a novel drug target to develop novel cancer therapy. We anticipate both direct mechanisms of action on the repair pathways and synthetic lethal interactions can be exploited for therapeutic benefit. The series of novel small molecule inhibitors that we have developed targeting RPA and XPA proteins independently exhibit single-agent anti-cancer activity in cancer cell lines, and potentiate cellular sensitivity to chemotherapeutic agent. Data demonstrate that these novel inhibitors do not interact with DNA but directly bind the corresponding NER proteins. Our data demonstrate that this class of inhibitors can be further developed as an anti-cancer therapeutic with considerable potential to be used in conjunction with radiation therapy and other cancer therapies that induce DNA damage.This works was supported by NIH grants R01-CA180710 and R41-CA162648 and the Tom and Julie Wood Family Foundation.Citation Format: Navnath S. Gavande, Pamela S. VanderVere-Carozza, Tyler L. Vernon, Katherine Pawelczak, John J. Turchi. Development of small molecule inhibitors for cancer therapy by targeting RPA and XPA nucleotide excision repair proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1416. doi:10.1158/1538-7445.AM2017-1416

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