406228-55-5
406228-55-5 structure
- Name: A-385358
- Chemical Name: A-385358
- CAS Number: 406228-55-5
- Molecular Formula: C32H41N5O5S2
- Molecular Weight: 639.828
- Catalog: Signaling Pathways Apoptosis Bcl-2 Family
- Create Date: 2018-01-20 07:01:50
- Modify Date: 2024-01-03 23:48:09
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A-385358 is a selective inhibitor of Bcl-XL with Kis of 0.80 and 67 nM for Bcl-XL and Bcl-2, respectively.
| Name | A-385358 |
|---|---|
| Synonyms |
N-[(4-{[(2R)-4-(Dimethylamino)-1-(phenylsulfanyl)-2-butanyl]amino}-3-nitrophenyl)sulfonyl]-4-(4,4-dimethyl-1-piperidinyl)benzamide
Benzamide, N-[[4-[[(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]-4-(4,4-dimethyl-1-piperidinyl)- N-[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4,4-dimethylpiperidin-1-yl)benzamide |
| Description | A-385358 is a selective inhibitor of Bcl-XL with Kis of 0.80 and 67 nM for Bcl-XL and Bcl-2, respectively. |
|---|---|
| Related Catalog | |
| Target |
Bcl-xL:0.8 nM (Ki) Bcl-2:67 nM (Ki) |
| In Vitro | 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[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]. |
| Kinase Assay | FL5.12 cells suspended in EMB growth medium containing 4% fetal bovine serum (FBS) are incubated at 37°C for 1 hour in 10 μM A-385358. Compound concentration is determined by high-performance liquid chromatography before and after the 1-hour incubation following brief centrifugation. To analyze membrane-bound fractions following compound incubation, cells are washed once with 10 volumes of cold PBS and lysed with 4 mL of water. A-385358 concentration is determined from aliquots of lysate before and after centrifugation[1]. |
| Cell Assay | A549 cells (1×105) are plated in 96-well plates in medium containing 10% fetal bovine serum. Following attachment, A-385358 is added to one set of wells (final concentration of 50 μM in 10% FBS) and medium is added to another set. [3H]Paclitaxel (5 μM; 0.5 μCi/mL final concentration) is added to all wells and the cells are incubated at 37°C for various periods of time. For washout experiments, cells are exposed first to [3H]paclitaxel for 2 hours. The cells are washed once with medium and then incubated with fresh medium with or without 50 μM A-385358 at 37°C for various periods of time[1]. |
| Animal Admin | For efficacy studies, male CD-1 nude mice are inoculated with a 1:5 dilution of tumor brei in 50% Matrigel and analysis is conducted. A-385358 is delivered in a vehicle containing 5% Tween 80, 20% propylene glycol, and 75% PBS (pH 3.8). Paclitaxel is formulated according to the recommendations of the manufacturer. For combination therapy of paclitaxel plus A-385358, both drugs are administered i.p. with the paclitaxel given several hours before treatment with A-385358 (except for immunohistochemistry studies looking at expression of MPM-2 and caspase-3 wherein the two drugs are given simultaneously)[1]. |
| References |
| Density | 1.3±0.1 g/cm3 |
|---|---|
| Molecular Formula | C32H41N5O5S2 |
| Molecular Weight | 639.828 |
| Exact Mass | 639.254883 |
| LogP | 7.60 |
| Index of Refraction | 1.649 |
| Storage condition | 2-8℃ |