A 385358

Research use only, not for human use.

A 385358 is a potent, selective, cell-permeable Bcl-XL inhibitor with Ki of 0.8 nM.

A 385358 is a potent, selective, cell-permeable Bcl-XL inhibitor with Ki of 0.8 nM, displays >80-fold selectivity over Bcl-2 (Ki=64 nM); shows relatively modest single-agent cytotoxic activity against most tumor cell lines with an EC50 of <500 nM in cells dependent on Bcl-X(L) for survival; enhances the in vitro cytotoxic activity of numerous chemotherapeutic agents; significantly inhibits tumor growth in the A549 xenograft model.

A-385358 is a selective inhibitor of Bcl-XL with Kis of 0.80 and 67 nM for Bcl-XL and Bcl-2, respectively, in fluorescence polarization assays. Treatment of IL-3-deprived FL5.12/Bcl-XL 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-XL 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-XL cells. In addition, A-385358 is more effective at stimulating cytochrome c release from mitochondria isolated from FL5.12/Bcl-XL versus Bcl-2 cells.

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.

A385358

Angiogenesis

Bcl-2

Bcl-2

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406228-55-5

639.83

C32H41N5O5S2

>98% (HPLC)

DMSO : 125 mg/mL195.36 mM

O=C(NS(=O)(C1=CC=C(N[C@H](CCN(C)C)CSC2=CC=CC=C2)C([N+]([O-])=O)=C1)=O)C3=CC=C(N4CCC(C)(C)CC4)C=C3

N-[4-[[(2R)-4-(Dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonyl-4-(4,4-dimethylpiperidin-1-yl)benzamide

(-20℃)

With Ice Pack

≥ 2 years