Design and Discovery of Novel Selective RET Inhibitors with High Central Nervous System Penetration, Enhanced Pharmacokinetics, and Pharmacodynamics

RET (rearrangement during transfection) is a transmembrane glycoprotein receptor tyrosine kinase. In pathological conditions, the RET mutation, gene fusion, and overexpression result in aberrant RET signal transduction in tumor cells, which activates downstream pathways and promotes tumor growth and metastasis. Selective inhibition of RET kinase could effectively treat RET-driven cancers. In this manuscript, a series of selective RET kinase inhibitors with novel structures were designed, synthesized, and biologically evaluated. Among the screened inhibitors, compound FHND5071 demonstrated potent inhibitory activities against various RET kinases and related cell lines. The pharmacokinetic results showed that compound FHND5071 had a targeted distribution in lung, liver, and brain tissues, exhibited high central nervous system penetration, and enhanced pharmacokinetics and pharmacodynamics. Western blot analysis indicated that compound FHND5071 significantly inhibited the phosphorylation of RET and downstream molecules ERK and AKT in tumor tissues. Furthermore, compound FHND5071 markedly inhibited tumor growth, showing good in vivo efficacy and significant intracranial antitumor activity.