MKC-8866

• Catalog Number: ACM1338934590
• Product Name: MKC-8866
• CAS: 1338934-59-0
• Category: Inhibitors
• Description: MKC-8866, also known as IRE1-IN-8866, is an inhibitor of IRE1 RNase activity. MKC8866 strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1α-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa.
• Synonyms: MKC-8866; MKC 8866; MKC8866; IRE1-IN-8866; IRE1IN8866; IRE1 IN 8866; IRE1-IN8866; IRE1-IN 8866; IRE1IN-8866; IRE1IN 8866
• IUPAC Name: 7-Hydroxy-6-methoxy-4-methyl-3-(2-morpholino-2-oxoethyl)-2-oxo-2H-chromene-8-carbaldehyde
• Molecular Weight: 361.35
• Molecular Formula: C18H19NO7
• Canonical SMILES: O=CC1=C(O)C(OC)=CC2=C1OC(C(CC(N3CCOCC3)=O)=C2C)=O
• InChI: InChI=1S/C18H19NO7/c1-10-11-7-14(24-2)16(22)13(9-20)17(11)26-18(23)12(10)8-15(21)19-3-5-25-6-4-19/h7,9,22H,3-6,8H2,1-2H3
• InChI Key: IFDGMRMUJYGWQQ-UHFFFAOYSA-N
• Solubility: Soluble in DMSO
• Appearance: Solid powder
• Shelf Life: >3 years if stored properly
• Storage: Dry, dark and at 0-4 °C for short term (days to weeks) or -20 °C for long term (months to years).
• Biological Target: MKC8866, a salicylaldehyde analog, is a potent, selective IRE1 RNase inhibitor with an IC50 of 0.29 μM in human vitro as well as strongly inhibits Dithiothreitol-induced X-box-binding protein 1-spliced (XBP1s) expression with an EC50 of 0.52 μM and unstresses RPMI 8226 cells with an IC50 of 0.14 μM.
• Drug Formulation: This drug may be formulated in DMSO
• Elemental Analysis: C, 59.83; H, 5.30; N, 3.88; O, 30.99
• Exact Mass: 361.1162
• HS Tariff Code: 2934.99.9001
• In Vitro Activity: First, to document the effects of MKC8866 on GL261 cells in vitro, it was evaluated whether MKC8866 blocked ER stress induced by tunicamycin (TUN, an inhibitor of protein N-glycosylation and inducer of ER stress). As expected MKC8866 treatment impaired IRE1 signals as assessed by the inhibition of XBP1 mRNA splicing upon treatment with the N-glycosylation inhibitor tunicamycin. To further document these results, the expression of a genuine XBP1s target gene, ERdj4, was evaluated. ERdj4 expression increased dramatically upon TUN treatment with kinetics compatible with the activation of XBP1s and attenuated upon MKC8866 treatment. No major change was observed upon TMZ treatment. MKC8866 did not affect TUN-induced ATF4 expression, indicating that MKC8866 did not impact on PERK signaling, another ER stress sensor. Finally, since treatment of GL261 cells with MKC8866 appeared to impact on the response of these cells to different stressors, the impact IRE1 RNase inhibition on cell sensitivity to TMZ was evaluated. GL261 cells' sensitivity to TMZ was increased upon treatment with MKC8866, phenomenon further amplified with combined irradiation. These results suggest that TMZ-induced damages to the cells promote the activation of IRE1 dependent adaptive signals that if blocked by MKC8866, decrease the cell ability to cope with TMZ treatment.; Reference: Cancer Lett. 2020 Dec 1;494:73-83. https://pubmed.ncbi.nlm.nih.gov/32882336/
• In Vivo Activity: To test whether the adjuvant use of MKC8866 could impact on mouse survival, the combination of this inhibitor with Stupp-like treatment using the fibrin-collagen gel plug as delivery tool was evaluated. In the first instance the impact of MKC8866, Stupp-like treatment and combined therapy on tumor morphology at sacrifice was evaluated. Tumors developing in the presence of the MKC8866 containing plug and upon Stupp-like treatment presented a totally different phenotype from those developing under Stupp-like treatment alone. This phenotype corresponded to much smaller tumors with tumor escape significantly delayed. Furthermore, when necrosis was measured in tumors collected at sacrific, it was observed that the combination of Stupp-like treatment and MKC8866 yielded much important necrosis, reflecting treatment efficacy. It was found that MKC8866 yielded a significant increase of mice survival (of about 20%) compared to Stupp alone, however with no significant impact of the drug concentration used in the gel.; Reference: Cancer Lett. 2020 Dec 1;494:73-83. https://pubmed.ncbi.nlm.nih.gov/32882336/
• Shipping: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
• Stock Solution Storage: 0-4 °C for short term (days to weeks), or -20 °C for long term (months).