Abstract 1358: Discovery and optimization of potent and selective benzonaphthyridinone analogs as dual mTOR/ATR small molecular inhibitors for treatment of cancer

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Abstract The Mammalian Target of Rapamycin is a highly conserved Serine/Threonine protein kinase that plays a key role in several fundamental cellular processes such as growth, proliferation and metabolism. As a key node in the PI3K/AKT/mTOR signal pathway, mTOR is currently being actively investigated as a therapeutic target for the treatment of a variety of human cancers. Structurally, mTOR shares high sequence identity in the catalytic domain with other PIKK family kinases including PI3Ks, ATR, ATM, DNA-PK and SMG-1. ATR is an apical kinase in a cell cycle checkpoint pathway that monitors DNA integrity. Upon DNA damage, ATR activation results in cell cycle arrest and the initiation of DNA repair processes. Numerous studies have demonstrated that impairment of ATR function sensitizes cells to death in the presence of chemotherapeutic drugs or ionizing radiation. We hypothesized that a dual mTOR/ATR dual inhibitor might produce a profound apoptotic response in cells with impaired DNA-repair pathways. Starting from the recently developed small molecular ATP competitive mTOR selective inhibitor Torin1, a focused medicinal chemistry exploration of the benzonaphthyridinone structure furnished a library of compounds which was screened in a functional cellular assay for ATR inhibition. Biochemical characterization of select compounds using an immunoprecipitation assays for ATR and mTORC1 kinase activity confirmed that the compounds are dual mTOR/ATR inhibitors. Select compounds were characterized in proliferation assays using p53-deficient HCT-116 cell lines alone and in combination with ionizing radiation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1358. doi:10.1158/1538-7445.AM2011-1358