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MKC 204: IRE-1α Inhibitor

MKC 204 is a drug discovery program directed at a key biochemical signaling pathway that may play a role in a number of diseases, including cancer and inflammatory disease.

The endoplasmic reticulum is a subcellular compartment for the biosynthesis and folding of newly synthesized proteins. The process is tightly controlled by signaling molecules which regulate protein folding, protein degradation, and cell death. The unfolded protein response (UPR) is a signaling pathway in the endoplasmic reticulum that becomes activated when the protein folding process malfunctions.

The UPR is intended to restore normal cell function by halting protein production while molecular “chaperones” correct or remove the improperly folded proteins. When cellular stress continues for an extended period of time, the role of the UPR changes from restoring normal function to initiating programmed cell death (apoptosis). In this manner, the improperly functioning cell is removed from the body.

In myeloma cells and possibly other malignancies, the UPR is not properly regulated. In these cells, an enzyme known as IRE-1α (inositol-requiring enzyme-1) activates the XBP-1 (X-box binding protein-1) gene that enhances molecular chaperone activity and protein degradation. The result is that tumor cells escape apoptosis, proliferate, invade vital organs in cancer patients, and/or confer resistance to other therapies like chemotherapy, radiotherapy, and antiangiogenic drugs.

Inhibiting IRE-1α restores UPR function and enables apoptosis to proceed.

Using our proprietary IRE-1α assay, we have identified a novel class of specific endoribonuclease inhibitors. These compounds selectively antagonize IRE-1α in-vitro and inhibit XBP-1 activity in tumor cells and animals. These compounds are undergoing the preclinical evaluation needed to initiate human clinical trials.

Potential Applications

Potential applications of IRE-1α inhibitors include the treatment of:

  • B cell malignancies such as multiple myeloma
  • Breast, prostate, and pancreatic cancers
  • Autoimmune diseases such as rheumatoid arthritis and lupus
  • Neurodegenerative diseases
  • Ischemia-reperfusion, cardiovascular disease
  • Metabolic disorders