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MKC3946

Catalog No. TQ0101   CAS 1093119-54-0

MKC3946 is an effective and soluble IRE1α inhibitor which triggered modest growth inhibition in multiple myeloma cell lines.

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MKC3946 Chemical Structure
MKC3946, CAS 1093119-54-0
Pack Size Availability Price/USD Quantity
1 mg In stock $ 61.00
5 mg In stock $ 173.00
10 mg In stock $ 279.00
25 mg In stock $ 468.00
50 mg In stock $ 688.00
100 mg In stock $ 978.00
1 mL * 10 mM (in DMSO) In stock $ 159.00
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Purity: 99.97%
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Biological Description
Chemical Properties
Storage & Solubility Information
Description MKC3946 is an effective and soluble IRE1α inhibitor which triggered modest growth inhibition in multiple myeloma cell lines.
In vitro MKC-3946 blocks XBP1 mRNA splicing and exhibit cytotoxicity against AML cells. MKC-3946 inhibits XBP1S expression induced by tunicamycin (TM) in NB4 cells (B) and AML samples from patients [1]. MKC-3946 prevents the splicing of the XBP1 mRNA in response to ER stress caused by mutant proinsulin production [2]. MKC-3946 is an IRE1α endoribonuclease domain inhibitor that blocks XBP1 mRNA splicing and triggers modest growth inhibition in MM cells. MKC-3946 inhibits XBP1s expression induced by Tm in a dose-dependent manner while not affecting phosphorylation of IRE1α. MKC-3946 blocks XBP1 splicing and enhances cytotoxicity induced by bortezomib or 17-AAG. MKC-3946 (10μM) enhances ER stress-mediated apoptosis induced by bortezomib or 17-AAG, and enhances cytotoxicity of ER stressors, even in the presence of BMSCs or exogenous IL-6 [3].
In vivo MKC-3946 (100 mg/kg, i.p.) inhibits XBP1 splicing in a model of ER stress in vivo, associated with significant growth inhibition of MM cells, alone or with bortezomib. MKC-3946 markedly reduces MM tumor growth in the treatment versus the control group. Inhibition of XBP1 splicing by MKC-3946 is associated with decreased MM growth in vivo, alone or in combination with bortezomib [3].
Cell Research For each assay, the various numbers of cells (1,000 for cell proliferation and 10,000 for cell viability assays) are seeded in 96-well plates, followed by either vehicle (DMSO) or increasing concentrations of the drug. For detection of relative numbers of living cells, 10 μL of MTT (5 mg/mL) is added to each well, placed in an incubator for four hours, followed by centrifugation (1,000 rpm, 5 min); 100 μL of supernatant media from each well are carefully removed and 100 μL of SDS buffer (20% in water) is added to dissolve the crystals. Results are further read on the spectrophotometer machine at 570 nM wavelength. Half maximal inhibitory concentration (IC50) is calculated using the GraphPad Prism 5. A synergy of combination of two drugs is determined using the CalcuSyn software. The extent of drug interaction between the two drugs is determined using the combination index (CI) for mutually exclusive drugs. Different CI values are obtained when solving the equation for different concentrations of drugs. A CI of 1 indicates an additive effect, whereas a CI of <1denotes synergy. All experiments are repeated at least three times [1].
Animal Research CB17 SCID mice (48-54 days old) are injected subcutaneously with 1×10^7 RPMI 8226 cells mixed with Matrigel on day 0, and receive treatment for 21 days starting on day1. Mice are assigned into 4 groups (n=8): daily intraperitoneal injections of 100 mg/kg MKC-3946; intravenous injections of 0.15 mg/kg bortezomib twice a week; a combination of MKC-3946 intraperitoneally with bortezomib intravenously; and 10% HPBCD intraperitoneally with normal saline intravenously as vehicle control. Tumor volume is calculated from caliper measurements every 3 to 4 days; mice are killed when tumors reached 1.5 cm in length. Survival is evaluated from the first day of treatment until death [3].
Molecular Weight 380.46
Formula C21H20N2O3S
CAS No. 1093119-54-0

Storage

Powder: -20°C for 3 years | In solvent: -80°C for 1 year

Solubility Information

DMSO: 30 mg/mL (78.85 mM)

TargetMolReferences and Literature

1. Sun H, et al. Inhibition of IRE1α-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia. Oncotarget. 2016 Apr 5;7(14):18736-49. 2. Zhang L, et al. IRE1 inhibition perturbs the unfolded protein response in a pancreatic β-cell line expressing mutant proinsulin, but does not sensitize the cells to apoptosis. BMC Cell Biol. 2014 Jul 10;15:29. 3. Mimura N, et al. Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma. Blood. 2012 Jun 14;119(24):5772-81.

Related compound libraries

This product is contained In the following compound libraries:
Anti-Cancer Active Compound Library Bioactive Compounds Library Max NO PAINS Compound Library Anti-Cancer Compound Library Cell Cycle Compound Library Endoplasmic Reticulum Stress Compound Library Covalent Inhibitor Library Bioactive Compound Library Hematonosis Compound Library Anti-Aging Compound Library

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Keywords

MKC3946 1093119-54-0 Cell Cycle/Checkpoint IRE1 Inositol requiring enzyme 1 inhibit Inhibitor MKC-3946 MKC 3946 inhibitor

 

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