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Purity: ≥98%
MKC3946(also known as MKC-3946) is a soluble and strong IRE1α RNase inhibitor with possible anticancer properties. The ability of cancer cells to withstand stress caused by the build-up of misfolded proteins in the endoplasmic reticulum (ER) is dependent on the unfolded protein response (UPR). A major UPR branch, the IRE1α-XBP1 pathway, is triggered in a large number of cancers. The IRE1α RNase inhibitor [MKC-3946, 2-hydroxy-1-naphthaldehyde (HNA)] demonstrated cytotoxicity towards AML cells and prevented the splicing of XBP1 mRNA. At least in part, the inhibition of IRE1α resulted in caspase-dependent apoptosis and G1 cell cycle arrest through the control of chaperone proteins, G1 phase controlling proteins (p21cip1, p27kip1, and cyclin D1), and Bcl-2 family proteins. The IRE1α inhibitors did not inhibit the growth of murine bone marrow cells with Xbp1 deletion. AML cytotoxicity linked to p-JNK induction and p-PI3K and p-MAPK reduction was observed when HNA was combined with either bortezomib or AS2O3. AML cells expressed more miRs, including miR-34a, when IRE1α RNase activity was inhibited. The cell became resistant to HNA when miR-34a was inhibited. Our findings clearly indicate that one promising therapeutic strategy for treating AML is to target pro-survival pathways driven by IRE1α.
| Targets |
IRE1α endoribonuclease
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| ln Vitro |
MKC-3946 causes mild growth inhibition in MM cell lines while having no harmful effects on healthy mononuclear cells. Crucially, it amplifies the cytotoxicity caused by 17-AAG or bortezomib considerably, even when external IL-6 or bone marrow stromal cells are present. XBP1s is induced by both 17-AAG and bortezomib, indicating ER stress, which is inhibited by MKC-3946. MKC-3946 increases the apoptosis brought on by these agents and is linked to an increase in CHOP. Treatment with MKC-3946 does not impede the function of IRE1α kinase or the binding of activated IRE1α to TRAF2 and subsequent JNK signaling[1].
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| ln Vivo |
MKC-3946 significantly inhibits the growth of MM cells in a model of in vivo ER stress by inhibiting XBP1 splicing[1].
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| Cell Assay |
For three hours, RPMI 8226 cells are either treated with or without Tm (5 μg/mL) in addition to MKC-3946 (0-10μM). After extracting total RNA, XBP1 and β-actin mRNA are assessed via RT-PCR.
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| Animal Protocol |
CB17 SCID mice (48-54 days old) are treated for 21 days beginning on day 1 after receiving a subcutaneous injection of 1×107 RPMI 8226 cells mixed with Matrigel on day 0. Four groups (n=8) of mice are allocated to receive daily intraperitoneal injections of 100 mg/kg MKC-3946; twice-weekly intravenous injections of 0.15 mg/kg bortezomib; a combination of intraperitoneal injections of MKC-3946 and intravenous injections of bortezomib; and intraperitoneal injections of 10% HPBCD with normal saline as a vehicle control. Mice are euthanized when tumors grow to a length of 1.5 cm. Tumor volume is estimated from caliper measurements every 3–4 days. From the moment of treatment initiation until death, survival is assessed.
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| References |
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| Molecular Formula |
C21H20N2O3S
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|---|---|---|
| Molecular Weight |
380.46
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| Exact Mass |
380.119
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| Elemental Analysis |
C, 66.30; H, 5.30; N, 7.36; O, 12.62; S, 8.43
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| CAS # |
1093119-54-0
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| Related CAS # |
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| PubChem CID |
59599728
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| Appearance |
White to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
591.6±50.0 °C at 760 mmHg
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| Flash Point |
311.6±30.1 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.695
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| LogP |
3.17
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
27
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| Complexity |
552
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C(=C([H])C([H])=C1C(N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])=O)C1C([H])=C([H])C2C(C([H])=O)=C(C([H])=C([H])C=2C=1[H])O[H]
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| InChi Key |
IVQVBMWPWPTSNO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H20N2O3S/c1-22-8-10-23(11-9-22)21(26)20-7-6-19(27-20)15-2-4-16-14(12-15)3-5-18(25)17(16)13-24/h2-7,12-13,25H,8-11H2,1H3
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| Chemical Name |
2-hydroxy-6-[5-(4-methylpiperazine-1-carbonyl)thiophen-2-yl]naphthalene-1-carbaldehyde
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (5.26 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6284 mL | 13.1420 mL | 26.2840 mL | |
| 5 mM | 0.5257 mL | 2.6284 mL | 5.2568 mL | |
| 10 mM | 0.2628 mL | 1.3142 mL | 2.6284 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
MKC-3946 is an IRE1α endoribonuclease inhibitor, which triggers modest cytotoxicity in MM cells.Blood.2012 Jun 14;119(24):5772-81. |
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MKC-3946 blocks XBP1 splicing and enhances cytotoxicity induced by bortezomib or 17-AAG.Blood.2012 Jun 14;119(24):5772-81. |
MKC-3946 enhances ER stress-mediated apoptosis induced by bortezomib or 17-AAG.Blood.2012 Jun 14;119(24):5772-81. |
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