UMI-77

UMI-77 is a selective Mcl-1 inhibitor, which shows high binding affinity to Mcl-1 (IC₅₀=0.31 μM). UMI-77 binds to the BH3 binding groove of Mcl-1 with K_i of 490 nM, showing selectivity over other members of anti-apoptotic Bcl-2 members. IC50 & Target: IC50: 0.31±0.11 μM (Mcl-1), 10.2±2.24 μM (Bcl-2), 36.09±13.80 μM (Bcl-xL)^[1]
Ki: 0.49±0.06 μM (Mcl-1), 5.33±1.0 μM (A1/Bfl-1), 8.19±1.91 μM (Bcl-w), 23.83±1.81 μM (Bcl-2), 32.99±4.33 μM (Bcl-xL)^[1] In Vitro: Competitive binding curve of UMI-77 against Mcl-1 is obtained by FP based binding assay using fluorescent labeled Bid BH3 peptide with an IC₅₀ of 1.87±0.22 μM. UMI-77 potently inhibits the cell growth of BxPC-3 and Panc-1 cell lines with IC₅₀ values of 3.4 μM and 4.4 μM respectively, and shows 3 to 5 times less potency in inhibition of the cell growth of two other tested cell lines MiaPaCa-2 (12.5 μM) and AsPC-1 (16.1 μM). The cell growth inhibition potency of UMI-77 correlates with the highest expression of Mcl-1 and Bak, and lowest expression of Bcl-xL in the sensitive cell lines, BxPC-3 and Panc-1. Capan-2 cells are showing similar sensitivity to UMI-77 (IC₅₀ of 5.5 μM) as BxPC-3 and Panc-1, although has low Mcl-1 levels^{[1]. In Vivo: 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].}