Definition

An orally bioavailable selective dual inhibitor of fusions and mutations involving the proto-oncogene receptor tyrosine kinase rearranged during transfection (ret) and the src family tyrosine kinases, with potential antineoplastic activity. Upon oral administration, the RET/SRC inhibitor TPX-0046 specifically targets and binds to ret mutants and ret-containing fusion products. This results in an inhibition of cell growth of tumor cells that exhibit increased ret activity. By inhibiting src kinase-mediated signaling and reducing the src-initiated recruitment of multiple receptor tyrosine kinases involved in bypass resistance, TPX-0046 may be able to overcome tumor resistance which may increase its therapeutic effect. Ret overexpression, activating mutations, and fusions result in the upregulation and/or overactivation of ret tyrosine kinase activity in various cancer cell types; dysregulation of ret activity plays a key role in the development and progression of these cancers. Src tyrosine kinases are upregulated in many tumor cells and play important roles in tumor cell proliferation, survival, migration, invasion and angiogenesis. Src upregulation is seen in tumors with acquired resistance to RET inhibitors.