Abstract 3235: Development of potent and selective inhibitors for ATR: An adjuvant for DNA damage based chemotherapeutics

Abstract

Abstract Inhibition of DNA damage checkpoint and repair function has been a challenging as well a promising approach in cancer therapy. ATR kinase is one of the key mediator of DNA damage response which induces cell cycle arrest and DNA repair via its downstream proteins. Blocking ATR has proved to prevent the Chk1 pathway from stalled replication fork and enhances the replication stress and premature mitotic entry. In addition inhibition of ATR can selectively sensitize the cancer cell to radio and chemotherapy, due to defective DNA damage signaling through the loss of ATM or p53 mutation in cancer cell. Due to its inherent role in DDR, ATR has been explored as a potential target in enhancing the effect of radiation and chemo-therapy in addition enables highly selective targeting the cancer cell through synthetic lethality. Despite the attractiveness of ATR inhibition in the cancer therapy, specific ATR inhibitors have remained indefinable. Further, there is a limited proof of concept data for ATR inhibition. Considering these facts and challenges we will be presenting some preliminary results with respect to In-silico design, synthesis and evolution of potential and selective inhibitors for ATR. References Llona-Minguez, S., Hoglund, A., Jacques, S. A., Koolmeister, T. & Helleday, T. Chemical strategies for development of ATR inhibitors. Expert Rev Mol Med 9, 10 (2014). Wagner, J. M. & Kaufmann, S. H. Prospects for the Use of ATR Inhibitors to Treat Cancer. Pharmaceuticals 3, 1311-1334 (2010). Liu, Q. et al. Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR. Cancer Res 73, 2574-2586 (2013). Citation Format: Sivapriya Kirubakaran, Vijay Thiruvenkatam Thiruvenkatam, Althaf Shaik. Development of potent and selective inhibitors for ATR: An adjuvant for DNA damage based chemotherapeutics [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 3235. doi:10.1158/1538-7445.AM2017-3235