The endoplasmic reticulum (ER) stress response is a cytoprotective mechanism activated in response to proteotoxic burden and is crucial for homeostatic regulation. IRE-1 is an ER-resident dual kinase/RNase that splices 26 nucleotides from the mRNA of the transcription factor XBP-1. This spliced XBP-1 mRNA variant encodes a functional 54-kDa, which translocates into the nucleus and regulates ER stress response genes, contributing to tumor progression. Until recently, the functional roles of the ER stress response pathways in chronic lymphocytic leukemia (CLL) had been largely overlooked because CLL cells do not develop a prominent ER structure. However, our studies have shown that CLL growth and survival is highly dependent on hyperactivation of the IRE-1/XBP-1 pathway. Here, we present our efforts to target XBP-1s expression though direct inhibition of IRE-1 RNase activity (J. Med. Chem. 2014, 57, 4289; J. Clin. Inv. 2014, 124, 2585). A series of novel formylated tricylic chromenones was synthesized via a Duff reaction that is attended by an unusual intramolecular cyclization. Using an in vitro FRET-suppression assay, we identified several potent inhibitors (IC50 0.05 – 1 uM) of IRE-1-induced XBP-1 mRNA splicing that also block XBP-1s expression and bind directly to endogenous IRE-1 in whole cells. Chemical optimization of our lead inhibitor using a prodrug strategy led to B-I09, which inhibits the growth of Eu-TCL1 mouse CLL cells as well as CLL cells freshly isolated from human patients. Since inhibition of the IRE-1/XBP-1 pathway compromises BCR signaling, we demonstrated that B-I09 and related compounds synergize with the BTK inhibitor ibrutinib to induce apoptosis in various B-cell cancer cell lines. Efforts toward the development of related IRE-1 inhibitors with enhanced efficacy in a transgenic mouse model of CLL will also be discussed.

Small molecules targeting XBP-1s expression in CLL

249th National Meeting (2015)

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