MKC8866 (IRE-1α inhibitor 1) (Synonyms: Orin1001) |
Catalog No.GC32889 |
MKC8866 (IRE-1α inhibiteur 1), un analogue du salicylaldéhyde, est un puissant inhibiteur sélectif de l'IRE1 RNase avec une IC50 de 0,29μ M in vitro humain. MKC8866 (IRE-1α inhibiteur 1) inhibe fortement l'expression de la protéine de liaison À la boÎte X 1 épissée induite par le dithiothréitol (XBP1) avec une CE50 de 0,52μ M et soulage les cellules RPMI 8226 avec une IC50 de 0,14μ M. MKC8866 (IRE-1α inhibiteur 1) inhibe l'IRE1 RNase dans les cellules cancéreuses du sein, entraÎnant une diminution de la production de facteurs pro-tumorigènes et peut inhiber la croissance tumorale du cancer de la prostate (PCa).
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Cas No.: 1338934-59-0
Sample solution is provided at 25 µL, 10mM.
MKC8866 is an inositol requiring enzyme 1 (IRE-1α) inhibitor with an IC50 of less than 0.1 μM.
Protein folding stress in the endoplasmic reticulum of a cell initiates a signal transduction cascade termed the unfolded protein response or UPR. A key enzyme, inositol requiring enzyme 1 (IRE-1α), relieves protein folding stress by enhancing molecular chaperone activity and therefore protects cells from stress induced apoptosis. MKC8866 is useful for treating at least B cell autoimmune diseases, certain cancers, and some viral infections. MKC8866 (Compound 167) inhibits IRE-1α in the in vitro assay with an IC50 of <0.1 μM. MKC8866 (Compound 167) IRE-1α in an in vivo XBP-1 splicing assay (e.g., in myeloma cells) with an EC50<10 μM[1].
MKC8866 is a selective IRE1 RNase inhibitor that exhibits acceptable pharmacokinetic and toxicity profiles. To determine the efficacy of MKC8866 treatment in vivo, MDA-MB-231 tumor xenografts are established in athymic nude mice. Once tumors have reached a palpable size (225-250 mm3), animals are randomized into treatment groups and treated with vehicle alone, 300 mg/kg MKC8866 alone, 10 mg/kg Paclitaxel alone or a combination of Paclitaxel and MKC8866. Treatments in all groups are administered until tumors reach maximal size (2000 mm3) or on day 60, whichever came first. MKC8866 is well tolerated after 60 consecutive oral doses and, based on pharmacokinetic allometric scaling, systemic exposures are well above anticipated clinical therapeutic levels. Following MDA-MB-231 tumor formation, mice are treated with Paclitaxel alone (7.5 mg/kg) for days 1-10, or a combination of Paclitaxel (days 1-10) and MKC8866 (300 mg/kg, days 1-28). After withdrawal of Paclitaxel treatment on day 10, an initial reduction in tumor volume is apparent in both treatment groups. Tumor re-growth, evident after day 18 in those animals receiving no further treatment, is repressed in the treatment group still receiving MKC8866. Tumor re-growth is only apparent in this group following cessation of MKC8866 on day 28[2].
[1]. Zeng, Qingping, et al. IRE-1α inhibitors. US9867803. [2]. Logue SE, et al. Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy. Nat Commun. 2018 Aug 15;9(1):3267.
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