AZD6738 Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
AZD 6738 is an orally bioavailable inhibitor of the serine/threonine protein kinase ataxia telangiectasia mutated (ATM) and Rad3-related (ATR; IC
50 = 1 nM). It can inhibit ATR substrate Chk1 Ser
345 phosphorylation in cells with an IC
50 value of 74 nM. AZD 6738 has been shown to inhibit the proliferation of various solid and hematological cell lines with IC
50 values of less than 1 μM and to reduce tumor growth in several ATM-deficient xenograft models. When used in combination with either DNA damaging chemotherapy agents or ionizing radiation, AZD 6738 demonstrated synergistic cell killing activity across multiple cell lines
in vitro and in xenograft studies.
Application
Ceralasertib (AZD6738) is a highly selective and potent ATR inhibitor that serves as a key sensor for the detection of DNA damage and a key activator of DNA damage checkpoints. Ceralasertib is currently in clinical development studies for the treatment of metastatic desmoplasia-resistant prostate cancer (mCRPC), advanced/metastatic melanoma, non-small cell lung cancer (NSCLC), prolymphocytic leukemia (PLL), and hairy cell leukemia (HCL), among other solid tumours.
Nebenwirkungen
Common side effects of AZD6738 include: anaemia, thrombocytopenia, neutropenia , increased risk of infection, bruising and bleeding, dizziness
diarrhoea, loss of appetite, changes in kidney function, tiredness
Feeling unwell or sickChanges in kidney function, feeling weak and lack of energy.
Enzyminhibitor
This orally active, and selective ATR kinase inhibitor (FW = 412.51 g/mol; CAS 1352226-88-0; Solubility: 80 mg/mL DMSO; < 1 mg/mL H2O) targets Ataxia Telangiectasia/Rad3-related kinase (IC50 = 1 nM), a serine/threonine protein kinase that activates checkpoint signaling upon genotoxic stresses (e.g., ionizing radiation, ultraviolet light, or replication stalling), thereby serving as a DNA damage sensor. In a model consisting of primary human Chronic Myelogenous Leukemia (CL) cells with biallelic TP53 or ATM inactivation xenotransplanted into NOD/Shi scid/IL-2Rγ mice, AZD6738 provides potent and specific inhibition of ATR signalling with compensatory activation of ATM/p53 pathway in cycling CLL cells in the presence of genotoxic stress. In p53 or ATM defective cells, AZD6738 treatment results in replication fork stalls and accumulation of unrepaired DNA damage, as evidenced by γH2AX and 53BP1 foci formation, carried through into mitosis and resulting in cell death by mitotic catastrophe. AZD6738 displays selective cytotoxicity towards ATM- or p53-deficient CLL cells. AZD6738 also potentiates cisplatin and gemcitabine cytotoxicity in Non-Small-Cell Lung Carcinoma (NSCLC) cell lines with intact ATM kinase signaling. It also potently synergizes with cisplatin in ATM-deficient NSCLC cells. When used in combination, cisplatin and AZD6738 resolve ATM-deficient lung cancer xenografts.
AZD6738 Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
