Definition

An orally bioavailable inhibitor of the tyrosine kinase BCR-ABL fusion oncoprotein, with potential antineoplastic activity. Upon oral administration, BCR-ABL inhibitor TGRX-678 specifically targets and binds to the myristate site at the C-terminal of the kinase domain, which results in the cross-linking of SH3 and SH2 domains to the kinase domain, and locks the kinase in its inactive state. This inhibits the activity of BCR-ABL, including the T315I gatekeeper residue mutation. The binding results in the inhibition of BCR-ABL-mediated proliferation and enhanced apoptosis of Philadelphia chromosome-positive (Ph+) hematological malignancies. The BCR-ABL fusion protein tyrosine kinase is an abnormal enzyme produced by leukemia cells that contain the Philadelphia chromosome. The T315I mutation, the most common BCR-ABL mutation, shows resistance to nearly all commonly used tyrosine kinase inhibitors (TKIs).