生物活性

• 靶点	ATR IC50:1nM

• 描述ATR/ATM kinases can phosphorylate a broad and overlapping catalogue of several thousand substrates in DNA damage signaling. The kinase activity of ATR, activated by single-stranded DNA (ssDNA) coated with replication protein A (RPA), is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). AZD6738 is a highly selective and potent inhibitor of ATR kinase activity with IC50 value of 1nM in isolated enzyme assay and showed inhibitory effect on ATR kinase-dependent cellular Chk1 phosphorylation with IC50 value of 74nM. AZD6738 impaired viability of the Kras mutant cell line, H23, H460, A549 and H358, with the lowest GI50 and greatest maximal inhibition in H460 and H23 cells (1.05μM, 88.0% and 2.38μM, 86.2%, respectively). Meanwhile, induced activation of ATM, as evident by increased pATM-S1981, stabilized p53 and expression of p21 and p27 can be observed in p53-wildtype H460 and A549 cells treated with 1μM AZD6738. A marked increase in pH2A.X-ser139 and cleaved PARP, indicative of accumulation of DNA damage and induction of apoptosis with greater sensitivity in cell viability assay, can be observed in H23 and H460 cells treated with AZD6738. Combination of AZD6738 (1μM) and cisplatin caused accumulation of cells in early S-phase and at the G1/S border, as well as dramatic cell death of H23 and H460 cells, suggesting its potent synergy with cisplatin in ATM-deficient cells independent of the ATM-p53 signaling pathway. Consistent with the in vitro study, daily administration of AZD6738 at dose of 25mg/kg for 14 consecutive days enhanced the therapeutic efficacy of cisplatin (3mg/kg) and caused rapid regression of ATM-deficient H23 tumors^[1].
• 作用机制AZD6738 is an ATP-competitive ATR inhibitor.^[2]

• 动物研究
  剂量	Mice: 25 mg/kg[2] (i.p.), 25 mg/kg[3] (p.o.); nude Mice[4] (p.o.): 75 mg/kg
  给药途径	i.p., p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03334617	Non-Small Cell Lung Cancer	Phase 2	Recruiting	July 30, 2021	-
  NCT03740893	Breast Neoplasm	Phase 2	Not yet recruiting	August 2023	United Kingdom ... more >> Royal Bournemouth Hospital Not yet recruiting Bournemouth, Dorset, United Kingdom, BH7 7DW Bristol Haematology and Oncology Centre Not yet recruiting Bristol, England, United Kingdom, BS2 8ED King's College Hospital London, England, United Kingdom, SE5 9RS Christie Hospital NHS Trust Not yet recruiting Manchester, England, United Kingdom, M20 4BX Belfast City Hospital Not yet recruiting Belfast, Northern Ireland, United Kingdom, BT9 7AB Velindre Cancer Center at Velinde Hospital Not yet recruiting Cardiff, Wales, United Kingdom, CF14 2TL Queen Elizabeth Hospital, University Hospitals Birmingham NHS Trust Not yet recruiting Birmingham, United Kingdom Guy's and St Thomas' Hospital NHS Foundation Trust Not yet recruiting London, United Kingdom, SE1 9RT Weston Park Hospital Not yet recruiting Sheffield, United Kingdom Collapse <<
  NCT02937818	Platinum Refractory Extensive-... more >>Stage Small Cell Lung Carcinoma Collapse <<	Phase 2	Recruiting	January 22, 2021	Germany ... more >> Research Site Not yet recruiting Gauting, Germany, 82131 Hungary Research Site Recruiting Kecskemét, Hungary, 6000 Research Site Recruiting Miskolc, Hungary, 3529 Research Site Recruiting Székesfehérvár, Hungary, 8000 Poland Research Site Recruiting Poznań, Poland, 60-569 Research Site Recruiting Warszawa, Poland, 02-781 Spain Research Site Recruiting Sevilla, Spain, 41009 Research Site Recruiting Valencia, Spain, 46009 Ukraine Research Site Recruiting Dnipropetrovsk, Ukraine, 49102 Research Site Recruiting Ivano-Frankivsk, Ukraine, 76018 Research Site Not yet recruiting Kirovograd, Ukraine, 25006 Research Site Active, not recruiting Sumy, Ukraine, 40022 Collapse <<

• 更多
• 参考文献

• [1] Vendetti FP, Lau A, et al. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Oncotarget. 2015 Dec 29;6(42):44289-305.