Mcl-1 (Myeloid cell leukemia-1) is an anti-apoptotic protein, which is a member of the Bcl-2 family. Mcl-1 is involved in the regulation of apoptosis versus cell survival, and in the maintenance of cell viability but not of proliferation. Mcl-1 mediates its effects by interactions with a number of other regulators of apoptosis[3].
UMI-77 is a Mcl-1 inhibitor. In FP-based binding assays, UMI-77 potently and selectively displaced fluorescent labeled BID-BH3 peptide from Mcl-1 protein. UMI-77 bound to the BH3 binding pocket of Mcl-1 and the Ki value was 0.49 μM[4]. In a pull-down assay, starting from the concentration of 10 μM , UMI-77 dose-dependently inhibited the interactions between BL-Noxa and cellular Mcl-1 in 2LMP cell lysates. In a SPR-based binding assay, it was reported that UMI-77 dose-dependently inhibited the binding of Mcl-1 to Bax with IC50 value of 1.43 μM. UMI-77 inhibited the growth of BxPC-2 and Panc-1 cells with IC50 values of 3.4 μM and 4.4 μM, respectively[4]. UMI-77 incubated at the concentrations of 3 μM or 10 μM for 48h induced apoptosis in esophageal squamous cell carcinoma KYSE150 and KYSE510 cells, as evidenced by cleavage of caspase-3 and PARP[5].
In BxPC-3 xenograft model established in SCID mice, UMI-77 administrated i.v. at the dose of 60 mg/kg for a total of 10 doses significantly inhibited tumor growth[4].
作用机制
UMI-77 is a Mcl-1 inhibitor. Docking and spectroscopy studies revealed that UMI-77 bound to the BH3 binding pocket of Mcl-1[4].
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