SH-BC-893
Cat. No.: DC12399
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Chemical Structure
1841409-92-4
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Field of application
SH-BC-893 is a water-soluble, orally bioavailable synthetic sphingolipid that triggers nutrient transporter internalization and also blocks lysosome-dependent nutrient generation pathways in cancer cells, activates protein phosphatase 2A (PP2A), leading to mislocalization of the lipid kinase PIKfyve; selectively kills cells expressing an activated form of the anabolic oncogene Ras in vitro and in vivo.SH-BC-893, increases the activity of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) up to 200-fold in vitro without permeabilizing endosomes. SH-BC-893 treatment trapped endocytosed oligonucleotides within extra-lysosomal compartments thought to be more permeable due to frequent membrane fission and fusion events. Simultaneous disruption of ARF6-dependent endocytic recycling and PIKfyve-dependent lysosomal fusion was necessary and sufficient for SH-BC-893 to increase non-lysosomal oligonucleotide levels and enhance their activity. In mice, oral administration of SH-BC-893 increased ASO potency in the liver by 15-fold without toxicity. More importantly, SH-BC-893 enabled target RNA knockdown in the CNS and lungs of mice treated subcutaneously with cholesterol-functionalized duplexed oligonucleotides or unmodified ASOs, respectively. Together, these results establish the feasibility of using a small molecule that disrupts endolysosomal trafficking to improve the activity of oligonucleotides in extrahepatic tissues.
| Cas No.: |
1841409-92-4 |
| Chemical Name: |
Chembl4440140 |
| Synonyms: |
Chembl4440140 |
| SMILES: |
Cl.OC[C@H]1[C@H](C2C=CC(=CC=2)CCCCCCCC)CCN1 |
| Formula: |
C19H32ClNO |
| M.Wt: |
325.916484832764 |
| Purity: |
>97% |
| Sotrage: |
2 years -20°C Powder, 2 weeks 4°C in DMSO, 6 months -80°C in DMSO |
| Publication: |
Simultaneous inhibition of endocytic recycling and lysosomal fusion sensitizes cells and tissues to oligonucleotide therapeutics-February 2023 Nucleic Acids Research
DOI:10.1093/nar/gkad023 |
| Description: |
SH-BC-893 is a water-soluble, orally bioavailable synthetic sphingolipid that triggers nutrient transporter internalization and also blocks lysosome-dependent nutrient generation pathways in cancer cells, activates protein phosphatase 2A (PP2A), leading to mislocalization of the lipid kinase PIKfyve; selectively kills cells expressing an activated form of the anabolic oncogene Ras in vitro and in vivo.SH-BC-893, increases the activity of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) up to 200-fold in vitro without permeabilizing endosomes. SH-BC-893 treatment trapped endocytosed oligonucleotides within extra-lysosomal compartments thought to be more permeable due to frequent membrane fission and fusion events. Simultaneous disruption of ARF6-dependent endocytic recycling and PIKfyve-dependent lysosomal fusion was necessary and sufficient for SH-BC-893 to increase non-lysosomal oligonucleotide levels and enhance their activity. In mice, oral administration of SH-BC-893 increased ASO potency in the liver by 15-fold without toxicity. More importantly, SH-BC-893 enabled target RNA knockdown in the CNS and lungs of mice treated subcutaneously with cholesterol-functionalized duplexed oligonucleotides or unmodified ASOs, respectively. Together, these results establish the feasibility of using a small molecule that disrupts endolysosomal trafficking to improve the activity of oligonucleotides in extrahepatic tissues. |
| References: |
Simultaneous inhibition of endocytic recycling and lysosomal fusion sensitizes cells and tissues to oligonucleotide therapeutics-February 2023 Nucleic Acids Research
DOI:10.1093/nar/gkad023 |
MSDS
COA
| LOT NO. |
DOWNLOAD |
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| 2018-0101 |
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| 2018-0101 |
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