An Mcl-1 inhibitor
AZD 5991 is an inhibitor of myeloid cell leukemia-1 (Mcl-1; IC50 = 0.72 nM).1 It is selective for Mcl-1 over Bcl-2, Bcl-xL, Bcl-W, and Bfl-1 (IC50s = 20, 36, 49, and 24 ?M, respectively). AZD 5991 decreases the viability of MV4-11 acute myeloid leukemia (AML) and MOLP-8 multiple myeloma (MM) cells with EC50 values of 24 and 33 nM, respectively. It disrupts formation of the Mcl-1-Bak complex and induces apoptosis in MOLP-8 cells when used at a concentration of 500 nM. AZD 5991 induces complete tumor regression in MV4-11 and MOLP-8 mouse xenograft models when administered at a single dose of 100 mg/kg.
1.Tron, A.E., Belmonte, M.A., Adam, A., et al.Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemiaNat. Commun.9(1)5341(2018)
Animal experiment: | Mice and Rats[1]In mice, drugs (e.g., AZD5991; 10-100?mg/kg) are dosed intravenously in a volume of 5?mL/kg except for Venetoclax that is dosed orally in a volume of 10?mL/kg. One million MV4-11, five million MOLP-8, ten million NCI-H929 or five million OCI-AML3 cells are injected subcutaneously in the right flank of mice in a volume of 0.1?mL. In rats, AZD5991 (10-100?mg/kg) is dosed intravenously in a volume of 10?mL/kg. Ten million MV4-11 cells are injected subcutaneously in the right flank of rats in a volume of 0.1?mL. Tumor volumes (measured by caliper), animal body weight, and tumor condition are recorded twice weekly for the duration of the study. The tumor volume is calculated[1]. |
参考文献: [1]. Tron AE, et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018 Dec 17;9(1):5341. | |
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