MKC3946 是一种有效的可溶性 IRE1α 抑制剂，可在多发性骨髓瘤细胞系中引发适度的生长抑制，可用于癌症研究。

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

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].

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].

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].

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].

1093119-54-0

C21H20N2O3S

380.46

DMSO:30 mg/mL (78.85 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years