tcsc0006108 A-385358

A-385358 is a selective inhibitor of Bcl-X_L with K_is of 0.80 and 67 nM for Bcl-X_L and Bcl-2, respectively.

IC50 & Target: Ki: 0.80 nM (Bcl-X_L), 67 nM (Bcl-2)

In Vitro: A-385358 is a selective inhibitor of Bcl-X_L with K_is of 0.80 and 67 nM for Bcl-X_L and Bcl-2, respectively, in fluorescence polarization assays. Treatment of IL-3-deprived FL5.12/Bcl-X_L cells for 24 hours with A-385358 results in cell killing with an EC₅₀ of 0.47±0.05 μM (n=68). This effect is accompanied by an increase in caspase-3 activity. Consistent with the greater affinity for the Bcl-X_L versus Bcl-2 hydrophobic grooves, the EC₅₀ of A-385358 for IL-3-depleted FL5.12/Bcl-2 cells (1.9±0.1 μM; n=55) is 4-fold higher relative to the cytokine-deprived FL5.12/Bcl-X_L cells. In addition, A-385358 is more effective at stimulating cytochrome c release from mitochondria isolated from FL5.12/Bcl-X_L versus Bcl-2 cells^[1].

In Vivo: The combination of A-385358 given at 100 mg/kg/d plus the lower dose of paclitaxel produces a significant reduction in tumor growth (%T/C) compare with paclitaxel monotherapy. This combination also yields a >100% increase in time for tumors to reach 900 mm³ (%ILS) compare with vehicle control. Maximal efficacy is observed during the dosing period for A-385358, with slow but steady increase in the tumor growth after termination of treatment. The combination of A-385358 at 75 mg/kg/d plus paclitaxel at 30 mg/kg/d is also well tolerated and inhibits tumor growth rate by nearly 80%. Significant effects on tumor growth relative to paclitaxel monotherapy are observed with doses as low as 50 mg/kg/d^[1].