Replication protein A targeted therapy: In vivo anticancer activity and cellular target engagement

Background: Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination and the DNA-damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival smoking-related cancers. These observations are consistent with increase serving an adaptive mechanism that allows tolerance genotoxic stress resulting from carcinogen exposure. Materials methods: We have employed chemical synthesis, vitro analyses vivo xenograft studies to assess action, cellular engagement therapeutic activity RPA-targeted agents. Results: discovered, developed characterized novel small molecule inhibitor (RPAi) NERx-329 blocks RPA-DNA interaction. optimized formulation studies. NERx 329 elicits single agent anticancer across broad spectrum cancers which allowed identification genetic predictors RPAi efficacy. knock out screen also identified additional alterations activity. series these models were pursued results demonstrate specific vivo. Chemical inhibition is shown potentiate DDR inhibitors well traditional damaging therapeutics. The cell cycle, chromatin-bound pathway activation on-target by NERx-329. Conclusions: targeting interaction state exhaustion In addition, sensitivity been will allow selection populations likely benefit Conflict interest: Ownership: JJT cofounder Biosciences. Board Directors: KSP serve on Biosciences BoDs.