Targeting the DNA Damage Response sensor Replication Protein A for first inclass cancer therapy

Abstract The DNA Damage Response (DDR) is an integrated network of DNA repair and cell signaling pathways that are critical towards maintaining genomic stability. Targeting the DDR for cancer therapy exploits two important vulnerabilities of many cancers. This first is that oncogenic replication stress induces DNA damage and genomic instability resulting in the reliance on DDR for cancer cell survival. The second is that many cancers harbor genetic defects in DDR and DNA repair pathway components that force the cancer cells to rewire the DDR and become reliant on compensatory pathways. This results in the opportunity for synthetic lethal interactions that can be exploited to specifically target cancer cells. The most successful DDR targeted therapies inhibit the DNA damage sensor, PARP, a protein that recognizes ssDNA breaks. With the initial clinical success of PARP inhibitors, development of DDR targeted therapeutics has become increasingly popular. However, the majority of the current approaches have targeted protein kinases that are downstream of the DNA damage sensors and the clinical outcomes with these therapeutics have not met expectations. NERx Biosciences has developed a novel strategy to realize the full therapeutic promise of the DDR, by intervening upstream of the DDR kinases and targeting specific DDR sensors. The human single stranded DNA (ssDNA) binding protein, replication protein A (RPA), is a critical sensor for the DDR and 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. Previous work employed chemical synthesis, in vitro analyses and in vivo xenograft studies to assess mechanism of action, cellular engagement and therapeutic activity of RPA-targeted agents. 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. The goal of this direct to Phase 2 application is to accelerate commercial readiness of this novel therapeutic toward IND approval. This goal will be met through three aims including formulation for oral delivery of NERx329, assessing pharmacokinetic, potency and safety of NERx 329, and initiating critical CMC work required for final IND. The key deliverables of each aim will provide a comprehensive data package that will ultimately position NERx Biosciences to complete final IND enabling studies for first-in-class and first-in-human trials of novel agents targeting RPA.