MKC3946

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.

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