Our study demonstrated that AZD1775 synergistically promotes VE-822-induced anti-leukemic activity in AML cell lines and provides support for clinical research on VE-822 in combination with AZD1775 for the treatment of AML patients. The specificity of LY2409881 for NF-B signaling is further studied in a cell-based assay, by examining the effect of LY2409881 in the TNF. In contrast, the IC 50 for IKK1 and other common kinases is at least one log higher. By in vitro kinase assay, LY2409881 potently inhibits IKK2, with an IC 50 of 30 nM. VE-822 combined with AZD1775 synergistically induced AML cell apoptosis and led to replication stress and DNA damage in AML cell lines. LY2409881 is an IKK2 inhibitor that inhibits TNF-induced activation of NF-B. VE-822 and AZD1775 decreased the protein levels of ribonucleotide reductase M1 (RRM1) and M2 (RRM2) subunits, key enzymes in the synthesis of deoxyribonucleoside triphosphate, which increased DNA replication stress. AZD1775 significantly promoted VE-822-induced inhibition of AML cell proliferation and led to a decreased number of cells in the G2/M phase. Our results showed that VE-822 inhibited AML cell proliferation and induced apoptosis in a dose-dependent manner. In this study, we investigated the anti-leukemic effects of VE-822 alone or combined with Wee1-selective inhibitor AZD1775 in AML cells.
The ATR-selective inhibitor VE-822 has proper solubility, potency, and pharmacokinetic properties.
Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of different types of DNA damage, which is crucial for the maintenance of genomic integrity. Resistance to standard induction therapy and relapse remain the primary challenges for improving therapeutic effects in acute myeloid leukemia (AML) thus, novel therapeutic strategies are urgently required.
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