Chaperomes are proteins that interact with other proteins to facilitate folding and other processes required for proper function. The chaperomes heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are involved in the processing of proteins that are critical for physiologic cellular function and replication. A network of molecular chaperones is known as the chaperome. Inhibition of the chaperome leads to diminished cellular replication, which is unregulated in cancer and in many immune-mediated diseases.
ADX-1612 and ADX-1615, Chaperome Inhibitors
Our investigational new drug ADX-1612 is a highly potent chaperome inhibitor that has completed numerous clinical trials in oncologic diseases. We intend to develop ADX-1612 for the treatment of systemic lymphoproliferative inflammatory diseases where excessive immune cell replication leads to inflammation, organomegaly, and other pathologies. ADX-1612 appears to be reasonably well tolerated at doses that may be sufficient to diminish immune cell replication.
The chaperome is active in autoimmune disease and is believed to lead to broad stimulation of the immune system. Preclinical results have shown the potential of ADX-1612 to diminish inflammatory cytokines, immune cell numbers, autoantibody formation, and lymphadenopathy (pathologic swelling of the lymph glands, in part due to immune cell hyper-proliferation). In addition, ADX-1612 appears to preserve organ function in animal models of autoimmune disease.
ADX-1612, and an oral pro-drug of ADX-1612 known as ADX-1615, in combination with DNA-damaging agents, may have utility in the treatment of certain cancers. The chaperome is required for DNA repair, and chaperome inhibition in the setting of chemotherapy-induced DNA damage could lead to substantial levels of cancer cell death. In ovarian cancer cell lines, preclinical studies have demonstrated the anti-proliferative synergy of ADX-1612 in combination with platinum-containing DNA damaging agents.