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  • A high throughput screening campaign led to the discovery

    2024-06-22

    A high-throughput screening campaign led to the discovery of the first series of both potent and selective ATR kinase inhibitors by Vertex Pharmaceuticals (Charrier et al., 2011). One of these compounds, VE-821, was shown to be a potent ATP-competitive inhibitor of ATR with minimal cross-reactivity against the related PIKKs ATM, DNA-PKcs and MTOR (Reaper et al., 2011). VE-821 inhibited phosphorylation of the ATR downstream target CHK1 at Ser345 and showed strong synergy with genotoxic agents from multiple classes in the colorectal cancer cell line HCT116. The observed chemosensitisation was most pronounced with DNA cross-linking agents such as cisplatin, and was further enhanced by knockdown of p53 expression, in ATM-deficient mmp inhibitor or in combination with the specific ATM inhibitor KU-55933. Importantly, VE-821 cytotoxicity in normal cells appeared minimal, causing only a reversible growth arrest without significant induction of cell death (Reaper et al., 2011). These findings are further supported by a study published earlier the same year, which demonstrated that genetic inhibition of ATR expression selectively enhanced cisplatin sensitivity in human colorectal cancer cells with inactivated p53 (Sangster-Guity et al., 2011). Together these studies further promote the concept that G1 checkpoint-deficient cancer cells might be more sensitive ATR kinase inhibition, especially in combination with genotoxic treatments. VE-821 has since been used in several studies and has consistently been shown to sensitise a variety of cancer cell lines to IR and chemotherapy (Pires et al., 2012, Prevo et al., 2012, Huntoon et al., 2013). Pires et al. demonstrated, that VE-821 enhanced IR-induced cytotoxicity in a panel of 12 human cancer cell lines. Notably, VE-821 radiosensitised cancer cells under severe hypoxia and over a range of oxygen concentrations (Pires et al., 2012). This is of particular interest, as hypoxic tumour cells are more resistant to radiotherapy (Wouters and Brown, 1997, Sprong et al., 2006) and therefore represent a major obstacle for the efficacy of radiotherapy. However, whether such a strategy is also effective in vivo is yet to be demonstrated. VE-822, an analogue of VE-821 with increased potency and selectivity against ATR, increased solubility and good pharmacokinetic properties was shown to potently radiosensitise pancreatic cancer cell lines in vitro. Furthermore, VE-822 treatment profoundly radiosensitised xenograft models of human pancreatic cancer and further increased the growth delay induced by IR combined with gemcitabine. Importantly, VE-822 was well tolerated in mice and did not enhance toxicity in normal cells and tissues (Fokas et al., 2012). VE-822 was the first selective ATR inhibitor to enter clinical development, and is now known as VX-970. In a recent study, published by Vertex Pharmaceuticals, VX-970 (VE-822) was shown to markedly sensitise a panel of non-small cell lung cancer cell lines, but not normal cells, to multiple DNA damaging drugs, namely cisplatin, oxaliplatin, gemcitabine, etoposide and SN38, the active metabolite of irinotecan. The sensitising effect of VX-970 was most evident with cisplatin and gemcitabine co-treatment, where >75% of the 35 tested cell lines were sensitised. Consistent with previous reports, the observed chemosensitisation was more pronounced in cells with p53-deficiency than in cells with retained p53 activity. In patient-derived lung tumour xenograft models, VX-970 significantly improved responses to cisplatin (in six out of the seven models) (Hall et al., 2014). These data suggest that VX-970 may have the potential to increase the efficacy of DNA damaging therapy in patients with lung cancer. A phase I clinical trial to assess the safety, tolerability and pharmacokinetics of VX-970 in combination with cytotoxic chemotherapy is currently ongoing (ClinicalTrials.gov: NCT02157792). A second ATR inhibitor currently in clinical development is AZD6738, developed by AstraZeneca. AZD6738 is an analogue of AZ20, a potent and selective ATR inhibitor which has been shown to possess substantial in vivo single agent activity in MRE11A-deficient LoVo xenografts at well tolerated doses (Jacq et al., 2012, Foote et al., 2013). AZD6738 possesses significantly improved solubility, bioavailability and pharmacokinetic properties compared to AZ20 and is suitable for oral dosing (Jones et al., 2013). It inhibits phosphorylation of the ATR downstream target CHK1 while increasing phosphorylation of the DNA DSB marker γH2AX in vitro. In vivo combination studies with carboplatin or IR demonstrated significantly increased anti-tumour growth inhibitory activity with this compound. Furthermore, AZD6738 showed single-agent anti-tumour activity in ATM-deficient but not ATM-proficient xenograft models (Guichard et al., 2013, Jones et al., 2013). This anti-tumour activity was associated with a persistent increase in γH2AX staining in tumour tissue but only a transient increase in normal tissues such as bone marrow or gut. This suggests that a favourable therapeutic index could be achieved, which is encouraging for the further development of this compound for the clinic. A phase I clinical trial to assess the safety of AZD6738 alone and in combination with radiotherapy in patients with solid tumours is currently recruiting (ClinicalTrials.gov: NCT02223923).