Abstract: The present invention directed to a method of treating multiple myeloma with the following compound: or a pharmaceutically acceptable salt thereof. The compound is a novel small molecule inhibitor of Ire1.

Abstract: Activation of the adaptive Ire1-XBP1 pathway has been identified in many solid tumors and hematological malignancies, including multiple myeloma (MM). What is disclosed is STF-083010, a novel small molecule inhibitor of Ire1. STF-083010 inhibited Ire1 endonuclease activity, without affecting its kinase activity, after ER stress both in vitro and in vivo. Treatment with STF-083010 showed significant anti-myeloma activity in model human MM xenografts. Similarly, STF-083010 was preferentially toxic to freshly isolated human CD138(+) MM cells when compared to other similarly isolated cell populations. The identification of this novel Ire1 inhibitor supports the hypothesis that the Ire1-XBP1 axis is a promising target for anti-cancer therapy, especially in the context of multiple myeloma.

Abstract: Compounds that are inhibitors of the unfolded protein response and endonuclease IRE1 are provided, together with compositions comprising such compounds, and methods for their use in the treatment of various disorders, such as cancer, autoimmune disorders, and diabetes. Also provided are packaged pharmaceuticals comprising these compositions. The compositions may be administered in combination with another therapeutic agent.

Abstract: Transgenic mammals, cells derived from the animals, and methods of using these to monitor the endoplasmic reticulum (ER) stress response are provided. In some embodiments, the methods allow for monitoring the ER stress response in real time. Some of the methods allow non-invasive in vivo visualization of ER stress response. Also provided are methods of screening molecules and/or treatment conditions for the ability to modulate the ER stress response, methods of treating diseases characterized by ER stress response activity, and methods of detecting the toxicity or therapeutic ratio of molecules that modulate the ER stress response.

Abstract: Compounds that are inhibitors of the unfolded protein response and endonuclease IRE1 are provided, together with compositions comprising such compounds, and methods for their use in the treatment of various disorders, such as cancer, autoimmune disorders, and diabetes. Also provided are packaged pharmaceuticals comprising these compositions. The compositions may be administered in combination with another therapeutic agent.

Abstract: Methods for identifying compounds that are inhibitors of the unfolded protein response are provided. In particular, the methods identify compounds that inhibit the activity of IRE1.

Abstract: Disclosed is a method of treating a solid tumor, where the tumor contains regions of hypoxic cells, either because of poor vascularization in the tumor or because of vasoconstrictive or vaso-occlusive measures brought to bear on the tumor. The method includes administering to a subject, a compound effective to activate protein kinase C activity in the cells of the tumor, via a route effective to direct the compound to such regions of hypoxia in the tumor. Preferred compounds include phorbol esters, diacylglycerols, and thapsigargin. Also disclosed is a vaso-occlusive composition containing a protein kinase C activator, for use in the treatment method.