Selective β1 Inhibitors

Oncorx Pharmaceuticals has developed high-affinity tricyclic phenothiazine drugs that selectively target β1 integrin that are overexpressed on the surface of therapy-resistant and glioma tumors. The expression of β1 integrin on the therapy-resistant cell surface creates an anchoring scaffold for a new dominant signaling pathway through β1 integrin subunit. Activation of β1 integrin plays a crucial role in regulating the epithelial-to-mesenchymal transition, anchorage-independent growth, the reorganization of the actin cytoskeleton and growth of cancer stem cells. 

Our high-affinity phenothiazine drugs have multiple effects in treating resistant tumors; 1) they inhibit the activation of STAT3;  2) they restore PTEN protein phosphatase activity to its normal suppressor function; and most importantly, 3) they disrupt the formation of actin filaments that are known regulate apoptosis and to interfere with cytotoxic killing by immune cells. Our high-affinity phenothiazine drugs markedly reduce the self-renewing cancer stem cell populations in a number of resistant triple-negative tumor cells and malignant melanoma cells.

Thioridazine, the most potent phenothiazine in tumor regulation, is well-known to cause genotoxicity, QT prolongation and life-threatening cardiac arrhythmias through its interaction with DNA and inhibition of several cardiac ion channels r4espectively. Thioridazine, and similar drugs in its chemical class, remain laboratory curiosities that have not been able to secure FDA approval. Oncorx pharmaceuticals has developed a first-in-class family of phenothiazine drugs that interact minimally with DNA, hERG K+ channels, Na+K+-ATPase channels and are low risk for toxixites caused by these interactions.

Oncorx Pharmaceuticals has additionally identified a previously un-recognized cause of life-threatening cardiotoxicities involving the generation of highly reactive oxygen (ROS) phenothiazine metabolites that are responsible for their genotoxicity, QT prolongation, cardiac arrhythmias and torsade de pointes. These metabolites are formed by the biotransformation of the parent phenothiazine to highly reactive quinoneimines through enzymatic conversion by myeloperoxidases in the patient's blood.  Oncorx Pharmaceuticals has developed a the firdt family of phenothiazine drugs that block the formation of these highly reactive oxygen metabolites. 

Cancer patients, unlike the general population, have a marked elevation of myeloperoxidase in their blood, making them a high-risk population for life-threatening cardiotoxicities involving the generation of highly reactive oxygen (ROS) .

Oncorx considers the elimination of  life-threatening cardiotoxicities and genotoxicities through the highly reactive oxygen (ROS)  a major achievements by the company that paves the way for the clinical development and FDA approval of its high-affinity β1 integrin  antagonists .