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

Cong-Cong Jia, Wang Chen, Zi-Li Feng, Zhao-Peng Liu

Future medicinal chemistry 2021 Jan

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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.

Citation

Cong-Cong Jia, Wang Chen, Zi-Li Feng, Zhao-Peng Liu. Recent developments of RET protein kinase inhibitors with diverse scaffolds as hinge binders. Future medicinal chemistry. 2021 Jan;13(1):45-62