IT-139: A Novel GRP78 Inhibitor

IT-139 (Sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)]) is Intezyne’s most developed asset with a mechanism that inhibits the ER stress-response protein—GRP78.

IT-139:  Mechanism of Action

IT-139 has a novel mechanism of action. It inhibits the stress-induction of the protein GRP78 in cancer cells. By targeting the stress-induction of GRP78, IT-139 does not affect normal cells. When levels of GRP78 are decreased in tumor cells, biological functions such as autophagy, cell survival, angiogenesis, invasion and metastasis are dysregulated and immune-modulation and tumor cell death are amplified.


GRP78:  An Important Target in Cancer

GRP78 is the master-regulator of the Unfolded Protein Response (UPR), a signaling pathway that allows cells to survive stressful conditions and evade toxic insult from cancer drugs.

Normal cells can survive low levels of GRP78, where the protein is responsible for protein folding and the regulation of cellular stress. Chemotherapy drugs stress cancer cells and those cells that express high levels of GRP78 survive and are resistant.  

The unique qualities of IT-139 allow it to down-regulate GRP78 in tumor cells WITHOUT affecting GRP78 regulation and production in normal cells.


IT-139:  TEchnical Overview

IT-139, sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)], is an intravenously administered small molecule. IT-139 was selected from a library of ruthenium (Ru) compounds and, although ultimately intended to be administered in combination with chemotherapy, has also shown promising single agent anti-cancer activity in preclinical models and in the clinic. In a US Phase 1 single agent study, 10 of 38 evaluable patients achieved stable disease with manageable side effects, while eight patients showed tumor size reduction, including a durable partial response. Even when administered as a single agent, IT-139 is active against a broad range of tumor types including breast, colon, esophageal, gastric, osteosarcoma, liver, and lung carcinomas. IT-139 is effective in many tumor cell lines tested that are resistant to platinums, anti-metabolites, anthracyclines, vinca alkaloids, and taxanes, and is synergistic with most classes of cancer treatments.


GRP78:  Technical Overview

GRP78 (BiP/HSPA5) belongs to the Heat Shock Protein 70 (HSP70) family and is regarded as an essential gene. GRP78 knockout mice die at embryonic day 3 while heterozygous mice remain viable, confirming normal cells can tolerate GRP78 down-regulation without adverse effect. GRP78 in normal cells is located in the endoplasmic reticulum where it facilitates the transport and correct folding of newly synthesized proteins, the exporting of misfolded proteins for degradation, and the binding of Ca2+ to maintain metabolic homeostasis. GRP78 is found in all cell types, but it is highly expressed in secreting cells such as thyroid and pancreatic islet cells. In tumor cells, GRP78 levels increase in the ER and the protein translocates to the cell surface, the cytosol, and the mitochondria. It is also secreted into the tissue stroma where it signals and interacts with the tumor microenvironment. These various locations coincide with the diverse biological activity of this protein in cancer cells making it an important target for cancer treatment.