UMI-77 acts as a small molecule inhibitor of Mcl-1 which blocks and attenuates pancreatic cell cancer growth. Anticancer agent.
umi-77 is a novel small-molecule inhibitor of mcl-1 with ki and ic50 values of 0.49 μm and 0.31 μm [1].myeloid cell leukemia-1 (mcl-1) is a member of the prosurvival bcl-2 family and is a potent anti-apoptotic protein. mcl-1 acts as an important survival factor in a broad range of human cancers [1].umi-77 is a novel small-molecule mcl-1 inhibitor. in fp-based binding assays, umi-77 potently and selectively displaced fluorescent labeled bid-bh3 peptide from mcl-1 protein with ki value of 0.49μm and bound to the bh3 binding pocket of mcl-1 protein. umi-77 bound to a1/bfl-1, bcl-w, bcl-2 and bcl-xl with ki values of 5.33, 8.19, 23.83 and 32.99μm. in a pull-down assay, umi-77 at 10 μm effectively and dose-dependently inhibited the interactions between bl-noxa and cellular mcl-1. it was reported that mcl-1 regulates pro-apoptotic bax and bak proteins and preventing their pro-apoptotic activity. umi-77 dose-dependently inhibited the binding of mcl-1 to bax with ic50 value of 1.43μm. in pc cells, umi-77 inhibited cell growth and induced apoptosis in a time and dose-dependent way [1].in bxpc-3 xenografted scid mice model, umi-77 exhibited robust anti-tumor efficacy with no toxicity. also, umi-77 decreased the anti-apoptotic protein survivin, which potently inhibited apoptosis by antagonizing caspase activity [1].
UMI-77 exhibits moderate metabolic stability with a half-life of 45 minutes.The maximum tolerated dose (MTD) of UMI-77 in SCID mice is determined. Administered 60 mg/kg i.v. for 5 consecutive days per week for two weeks does not cause any loss in the animal weight and there is no obvious sign of toxicity during the course of the treatment. Increasing the dose to 80 mg/kg show severe animal weight loss (>20%), therefore 60 mg/kg is used as a therapeutic dose for the in vivo efficacy studies. Daily treatment with UMI-77 for 5 consecutive days a week for two weeks results in statistically significant tumor growth inhibition by 65% and 56% in comparison with the controls in day 19 (p<0.0001) and day 22 (p<0.003) respectively[1].
Mcl-1: 0.49 μM (Ki); Bfl-1: 5.33 μM (Ki); Bcl-W: 8.19 μM (Ki); Bcl-2: 23.83 μM (Ki); Bcl-xL: 32.99 μM (Ki)
[1]. abulwerdi f, liao c, liu m, azmi as, et al. a novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo. mol cancer ther, 2014, 13(3): 565-575.
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