SH-BC-893 |enhance siRNAs and ASOs|DC Chemicals

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

2018-0101
2018-0101

Cat. No.	Product name	Field of application
DC60580	Endosidin5(ES5)	Endosidine 5 (ES5), is one of the most potent small molecules interferes with recycling endosomes through Annexin A6, thereby promoting the release and expression of mRNA into the cytoplasm. The delivered mRNAs is greatly enhanced via inhibition of endocytic recycling in cells and in live mice. NAV2729 (NAV) and endosidin 5 (ES5), resulted in significant enhancement (1.5–2 folds) of LNP-mediated delivery of Fluc mRNAs. Incubation of NAV and ES5 together caused modest further increases in Fluc expression in comparison to the sole application of either compound.
DC45847	ART558	ART558 is a nanomolar potent, selective, low molecular weight, allosteric DNA polymerase activity of Polθ inhibitor (IC50=7.9 nM). Inhibition of TMEJ with ART558 increases the efficiency of HDR-mediated repair on Cas9-induced DSBs, most profoundly in combination with a NHEJ/DNA-PKcs inhibitor.
DC36761	Bropirimine	Bropirimine is a synthetic agonist for toll-like receptor 7 (TLR7). Bropirimine inhibits differentiation of osteoclast precursor cells into osteoclasts via TLR7-mediated production of IFN-β. Bropirimine is an orally active immunomodulator that has demonstrated anticancer activity in transitional cell carcinoma in situ (CIS) in both the bladder and upper urinary Bropirimine could enhance the transfection efficiency to 2-fold to 5-fold of Lipofectamine 3000 and LNP, all of which are currently approved for clinical use in the treatment of the most common malignant tumors.
DC9284	SCH58261	SCH 58261 is a potent and selective A2a adenosine receptor antagonist with Ki of 2.3 nM and 2 nM for rat A2a and bovine A2a. SCH58261 could enhance the transfection efficiency to 2-fold to 5-fold of Lipofectamine 3000 and LNP, all of which are currently approved for clinical use in the treatment of the most common malignant tumors.
DC12399	SH-BC-893	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.
DC11971	NAV-2729（Grassofermata）	NAV 2729 (NAV2729) is a chemical potentiator for mRNA-LNPs, increasing the delivery efficiencies of mRNA-LNPs in vitro and in vivo.
DC8040	STAT3 Inhibitor XVIII, BP-1-102	BP-1-102 is a potent, orally bioavailable and selective STAT3 inhibitor.BP-1-102 could enhance the transfection efficiency to 2-fold to 5-fold of Lipofectamine 3000 and LNP, all of which are currently approved for clinical use in the treatment of the most common malignant tumors.
DC20278	AZD-7648	AZD-7648 is a potent and selective DNA-PK inhibitor. AZD7648,enhances HDR efficiency in CRISPR-Cas9 gene editing by shifting DNA repair from the error-prone NHEJ pathway to the precise HDR pathway, significantly improving gene targeting outcomes in human cells for effective ex vivo gene therapies.