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  • ep4 antagonist Several studies have demonstrated that deplet

    2022-12-02

    Several studies have demonstrated that depletion of functional ATR increases the sensitivity of cancer cells to oncogene-induced replication stress thereby hindering tumour growth and inducing extensive cell death (Gilad et al., 2010, Murga et al., 2011, Schoppy et al., 2012). Importantly, Schoppy et al. found that hypomorphic ATR signalling (reduced to 10% of normal levels) was sufficient to induce synthetic lethality in oncogenic RAS-driven tumours, while only minimally affecting normal bone marrow and intestinal homeostasis (Schoppy et al., 2012). This finding suggests that a low level of ATR activity may be sufficient to sustain viability of highly proliferative adult tissues and at the same time raises the possibility that complete inhibition of ATR kinase activity may not be required to cause substantial and selective toxicity in cancer cells. Most tumour cells are defective in the DNA damage induced G1 cell-cycle checkpoint through, for example, mutations in p53 or other components of the p53 pathway. This leads to a reliance of the cells on the intra-S-phase and G2/M checkpoints to arrest the ep4 antagonist following DNA damage induction to allow for repair of the damage and consequently cell survival (Kastan et al., 1992). Inhibition of ATR, which is an important mediator of the intra-S-phase and G2/M cell cycle arrest in such cells would therefore lead to a general loss of DNA damage checkpoints, causing DNA damage accumulation and pre-mature entry into mitosis leading to mitotic catastrophe and cell death. G1 checkpoint-proficient cells, however, would be spared. Several proof-of-principle studies utilising expression of kinase dead ATR protein have demonstrated that functional loss of ATR leads to abrogation of the DNA damage-induced G2/M cell cycle arrest and sensitisation of cells to IR and a variety of DNA damaging chemotherapeutic agents (Cliby et al., 1998, Nghiem et al., 2002, Caporali et al., 2004). Indeed, caffeine, an inhibitor of both ATM and ATR, sensitises cells to IR and provides further support to these findings (Blasina et al., 1999, Sarkaria et al., 1999). Overall, these data encouraged the search for, and the development of, more potent and selective ATR inhibitors (Table 2). The first report on ATR-selective small-molecule inhibitors was published in 2009. Nishida et al. reported that Schisandrin B, a naturally-occurring dibenzocyclooctadiene lignan found in the medicinal herb Schisandra chinensis was a selective inhibitor of ATR (Nishida et al., 2009). The authors demonstrated that Schisandrin B was able to abrogate UV-induced intra-S-phase and G2/M cell cycle checkpoints and increase the cytotoxicity of UV radiation in human lung cancer cells. However, the inhibitory potency against ATR was weak and required the use of high drug concentrations (30μM for cellular assays). A more potent ATR inhibitor, NU6027, was reported in 2011 and was demonstrated to sensitise several breast and ovarian cancer cell lines to IR and several chemotherapeutic agents (Peasland et al., 2011). But, this compound was originally developed as a CDK2 inhibitor and is not selective for ATR. Also in 2011, Toledo et al. reported the results of a cell-based compound library screening approach for the identification of potent ATR inhibitors (Toledo et al., 2011). One of the compounds identified to possess significant inhibitory activity against ATR kinase was NVP-BEZ235, a drug originally introduced as a highly potent dual inhibitor of PI3K and MTOR with considerable in vivo anti-tumour activity (Maira et al., 2008), NVP-BEZ235 has been demonstrated to markedly radiosensitive Ras-overexpressing tumours (Konstantinidou et al., 2010). However, in light of the finding that it also inhibits ATR (and to a lesser extend ATM and DNA-PKcs), it seems likely that inhibition of the DDR kinases rather than PI3K or MTOR contributed to the observed effects. The aforementioned study by Gilad et al. which demonstrated that ATR-depletion is particularly cytotoxicity in cells that overexpress oncogenic Ras is in agreement with this notion (Gilad et al., 2010). ETP-46464 and Torin 2 are additional examples of compounds which possess potent ATR inhibitory activity, but lack selectivity (Liu et al., 2011, Toledo et al., 2011).