Abstract 2588: M1774, a novel potent and selective ATR inhibitor, shows antitumor effects as monotherapy and in combination

Abstract

Abstract The protein kinase ataxia telangiectasia- mutated and Rad3-related (ATR) is an important component of the DNA Damage Response (DDR) and a key mediator of the replication stress response (RSR). ATR is recruited to and activated by single-stranded DNA, which commonly forms as a consequence of replication stress (RS). ATR activation and signaling coordinates a multifaceted response to RS, however if left unresolved, replication forks may collapse, form double-strand breaks (DSB), lead to chromosomal rearrangements and eventually cell death. Several chemotherapeutic agents act by increasing RS in tumor cells, by directly damaging the DNA and/or depleting cellular resources required for DNA replication. Increased RS may also result from activation of oncogenes that drive dysregulated replication, a hypoxic environment, or from defects in other repair pathways even in the absence of exogenous DNA damaging insults. Inhibition of ATR activity in cancer cells disables the RSR, potentially enhancing the cytotoxicity of DNA damaging interventions and causing efficacy as monotherapy against tumors with reliance on ATR activity. M1774 is a potent inhibitor of ATR protein kinase with high selectivity towards other protein kinases. A broad range of antiproliferative activities (ranging from ~20 nM to >1 µM) was observed in a cancer cell line panel in vitro. M1774 showed pronounced synergy in combination with several DNA-damaging drugs and inhibitors of the DNA damage response. In vivo efficacy studies confirmed the combination potential suggested from in vitro studies. Pronounced combination benefit with complete tumor growth inhibition/regression was observed in combination with different chemotherapies or targeted DDR pathway inhibitors. Furthermore, M1774 showed pronounced activity as monotherapy in tumor models with gene mutations that result in a reliance on ATR activity. Clinical evaluation is ongoing to investigate M1774 as monotherapy and in combination with niraparib in patients with advanced solid tumors (DDRiver Solid Tumors 301, NCT04170153). Citation Format: Astrid Zimmermann, Heike Dahmen, Thomas Grombacher, Ulrich Pehl, Andree Blaukat, Frank T. Zenke. M1774, a novel potent and selective ATR inhibitor, shows antitumor effects as monotherapy and in combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2588.