Ligand-based receptor tyrosine kinase partial agonists: new paradigm for cancer drug discovery?

Areas covered: In this review the author describes ligands of ErbB receptors that function as partial agonists for these receptors and antagonize the activity of full agonists for these receptors. The author provides insights into the mechanisms by which these ligands function as antagonists and discuss how these insights can be translated into screens for novel small molecule- and antibody-based antagonists of ErbB receptors that hold potential as targeted cancer chemotherapeutics. Expert opinion: While there have been numerous key findings in this field, the identification of the structural basis of ligand functional specificity is still of the greatest importance. While it is true that, with some notable exceptions, peptide hormones and growth factors have not been good platforms for oncology drug discovery, addressing the fundamental issues of antagonistic partial agonists for RTKs has the potential of steering oncology drug discovery in new directions. Mechanism-based approaches are emerging to enable the discovery of small molecule and antibody RTK partial agonists that may antagonize RTK signaling and may hold promise as targeted cancer chemotherapeutics.