Cells operate a signaling network termed the unfolded protein response (UPR) to monitor protein-folding capacity in the endoplasmic reticulum (ER). Inositol-requiring enzyme 1 (IRE1) is an ER transmembrane sensor that activates the UPR to maintain the ER and cellular function. Although mammalian IRE1 promotes cell survival, it can initiate apoptosis via decay of antiapoptotic miRNAs[2]. MKC8866, a salicylaldehyde analog, is a potent, selective IRE1 RNase inhibitor with an IC50 of 0.29 μM in human vitro. MKC8866 strongly inhibits DTT-induced X-box-binding protein 1-spliced (XBP1s) expression with an EC50 of 0.52 μM and unstressed RPMI 8226 cells with an IC50 of 0.14 μM[3]. MKC8866 (0.2-10 μM; 3 days) suppresses the viability of all four cell lines in a dose-dependent manner under normal conditions, with the most robust effect in LNCaP cells and MKC8866 (20 μM; 72 hours) is sufficient to completely block paclitaxel-induced expression of XBP1s[3]. MKC8866 inhibits IRE1 RNase in breast cancer cells leading to the decreased production of pro-tumorigenic factors and it can inhibits prostate cancer (PCa) tumor growth[4]. In female athymic nude mice with MDA-MB-231 tumor, MKC8866 (oral 300 mg/kg for 28 days) reduced tumor regrowth post-paclitaxel withdrawal[3].
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