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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The RET proto-oncogene encodes a receptor tyrosine kinase crucial for cell growth and survival.
• Aberrant RET activation through mutations or fusions drives cancers, notably in lung and thyroid tissues.

Purpose of the Study:

• To review the progress in developing small molecule inhibitors targeting the RET protein kinase over the past 10 years.
• To classify these inhibitors based on their chemical structures and hinge-binding motifs.

Main Methods:

• Literature review of scientific publications and patents concerning RET inhibitors.
• Classification of inhibitors by chemotype, including pyrimidines, indolinones, and others.
• Analysis of biological activity, structure-activity relationships (SAR), and proposed binding modes.

Main Results:

• Identified and categorized diverse small molecule RET inhibitors based on hinge binder chemotypes.
• Summarized biological activities, SAR, and potential binding interactions for each inhibitor class.
• Highlighted the evolution of RET inhibitor development over the last decade.

Conclusions:

• Significant advancements have been made in the development of small molecule RET kinase inhibitors.
• Understanding the diverse chemotypes and their interactions provides a foundation for future targeted cancer therapies.
• Continued research into RET inhibitors holds promise for improved treatment strategies for RET-driven cancers.