Targeting kinases with DNA-encoded libraries: current landscape and future directions

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Biotechnology

Background:

• Kinase inhibitors are crucial for targeted cancer therapy.
• DNA-encoded libraries (DELs) offer a powerful platform for hit identification.
• Advances in DEL technology have expanded its application in drug discovery.

Purpose of the Study:

• To review and analyze kinase inhibitors discovered via DELs from 2009-2025.
• To highlight chemical diversity, binding interactions, and optimization strategies.
• To map targeted kinase families and discuss therapeutic applications.

Main Methods:

• Literature review of DEL-based kinase inhibitor discovery.
• Analysis of chemical structures, physicochemical properties, and binding modes.
• Case study evaluation of selected inhibitors and optimization approaches.

Main Results:

• Compilation of 47 initial hits and 17 leads for 24 kinase targets across 19 families.
• Characterization of chemical diversity and binding interactions.
• Identification of frequently targeted kinase families and successful therapeutic strategies.

Conclusions:

• DELs are effective for discovering selective and potent kinase inhibitors.
• Further advancements in DEL technology can accelerate kinase-targeted drug development.
• This review provides insights for future DEL-based drug discovery efforts.