Protein kinases: From targets to anti-cancer drugs.

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Protein kinases regulate cell signaling, with roles in diseases like cancer and diabetes.
• Early skepticism regarding adenosine tri-phosphate (ATP) competitor selectivity has been overcome.
• Advances in genomics and structural biology enable kinase classification and inhibitor design.

Purpose of the Study:

• To review the challenges and advancements in developing selective kinase inhibitors.
• To highlight the importance of structural and phylogenetic data in kinase-targeted drug discovery.
• To discuss strategies for target selection, molecule optimization, and clinical assay development.

Main Methods:

• Analysis of structural and phylogenetic data of protein kinases.
• Review of clinical development and market data for kinase inhibitors.
• Examination of small molecule inhibitor screening methodologies.
• Discussion of assay development for clinical assessment.

Main Results:

• Identification of distinct kinase classes based on inhibitor selectivity profiles.
• Discovery of novel binding modes enhancing inhibitor selectivity and potency.
• Validation of kinase inhibitors in clinical development and on the market.
• Recognition of key interactions through abundant structural data.

Conclusions:

• Despite challenges, significant progress has been made in developing selective kinase inhibitors.
• Leveraging structural insights is key to overcoming hurdles in kinase-targeted drug discovery.
• Future efforts must focus on optimizing target selection, molecule properties, and clinical validation.