Recent developments of RET protein kinase inhibitors with diverse scaffolds as hinge binders

RET is a proto-oncogene encoding a receptor tyrosine kinase. RET regulates key aspects of cellular proliferation, differentiation and survival. The activation of RET via gene fusions or point mutations is closely related to lung, thyroid and other cancers. This review summarizes the developments of a diversity of small molecule RET protein kinase inhibitors in the past 10 years. These RET inhibitors are classified according to their hinge binder chemotypes as: pyrimidines, including the pyrazolopyrimidines, pyrimidine oxazines, quinazolines, 4-aminopyrimidines and 4-aminopyridines; indolinones; 5-aminopyrazole-4-carboxamides; 3-trifluoromethylanilines; imidazopyridines, imidazopyridazines and pyrazopyridines; nicotinonitriles; pyridones and 1,2,4-triazoles. In each section, the biological activities of the inhibitors, their structure-activity relationships and possible binding modes with the RET kinase are introduced.

Automated summary

RET is a proto-oncogene encoding a receptor tyrosine kinase, activation of which is closely related to various cancers. In the past 10 years, a variety of small molecule RET protein kinase inhibitors have been developed and classified based on their chemical types, each with different structure-activity relationships.