Background:Rearranged during transfection (RET) is a receptor tyrosine kinase and a bona
fide oncogene that drives various cancers. Oncogenic RET induces abnormal activation of RET kinase,
causing tumorigenesis. RET can be abnormally activated through RET point mutations and RET fusions.
Although RET kinase has been discovered in tumors more than 30 years ago, patients with RET-altered
tumors gain limited benefits from multikinase inhibitors (MKIs). In 2020, pralsetinib and selpercatinib
were approved by FDA for the treatment of RET-altered tumors.Objective:Recently reported RET inhibitors were reviewed to provide an overview of the development of
novel RET inhibitors.Methods:Literatures, patents, and conference proceedings published in the past five years were collected.
Only RET inhibitors with novel scaffolds or in vivo efficacy were discussed in this review. The enzymebased
and cell-based activities, PK profiles, antitumor activities in vivo, and clinical efficacy of the selected
RET inhibitors were described.Results:Great efforts have been spent on the development of RET inhibitors, leading to increased RETtargeted
therapies. Due to high potency and specificity, pralsetinib and selpercatinib resulted in a >8-
month improvement in overall survival, compared to MKIs. However, solvent-front mutants emerged and
contributed to the acquired resistance to pralsetinib and selpercatinib. To overcome solvent front mutants,
TPX-0046, TAS0953, and LOX-260 are investigated in early clinical studies.Conclusion:Zeteletinib, SYHA1815, TPX-0046, TAS0953, and LOX-260 are potential therapies for
RET-altered cancers. In addition, macrocyclic inhibitors, allosteric inhibitors, and PROTACs are three
promising strategies to address the potential drug resistance of RET.