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Updated: Sep 18, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Design and Discovery of Novel Selective RET Inhibitors with High Central Nervous System Penetration, Enhanced
Xueyuan Wang1, Hang Miao1, Xinran Ye2
1College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, P.R. China.
Abstract:
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.
Insights
A novel RET kinase inhibitor, FHND5071, effectively targets RET-driven cancers. This compound shows potent inhibition, good pharmacokinetics, and significant antitumor activity, including in the central nervous system.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The RET receptor tyrosine kinase plays a crucial role in tumor development when aberrantly activated through mutation, fusion, or overexpression.
- Targeted inhibition of RET kinase presents a promising therapeutic strategy for RET-driven malignancies.
Purpose of the Study:
- To design, synthesize, and evaluate novel selective RET kinase inhibitors.
- To assess the efficacy and pharmacokinetic properties of a lead compound, FHND5071, in preclinical models.
Main Methods:
- Design and synthesis of novel chemical entities targeting RET kinase.
- In vitro biological evaluation of inhibitory activity against RET kinases and cancer cell lines.
- Pharmacokinetic, pharmacodynamic, and in vivo efficacy studies, including central nervous system penetration assessment.
Main Results:
- Compound FHND5071 demonstrated potent inhibition of various RET kinases and relevant cell lines.
- FHND5071 exhibited favorable pharmacokinetics with targeted tissue distribution (lung, liver, brain) and enhanced CNS penetration.
- Western blot analysis confirmed inhibition of RET phosphorylation and downstream signaling (ERK, AKT); FHND5071 showed significant in vivo antitumor efficacy, including intracranial activity.
Conclusions:
- FHND5071 is a potent and selective RET kinase inhibitor with promising therapeutic potential for RET-driven cancers.
- The compound's favorable pharmacokinetic profile and demonstrated efficacy in preclinical models, including CNS penetration, support its further development.
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