Fast Iterative Synthetic Approach toward Identification of Novel Highly Selective p38 MAP Kinase Inhibitors

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• p38 mitogen-activated protein kinases (MAPKs) are crucial in cellular responses to environmental stress.
• These kinases are implicated in inflammatory diseases and cancer, making them therapeutic targets.
• Existing p38 inhibitors lack high selectivity, particularly for type-II inhibitors targeting an inactive kinase state.

Purpose of the Study:

• To analyze the structural features of VPC-00628 responsible for its potency and selectivity.
• To identify novel, highly selective type-II p38α/β inhibitors.
• To develop a chemical probe for targeting the inactive state of p38α/β kinases.

Main Methods:

• Structure-activity relationship analysis of VPC-00628.
• Systematic combinatorial synthesis approach.
• In vitro assays to determine kinase inhibition and TNF-α release in whole blood.

Main Results:

• Identified key chemical building blocks in VPC-00628 for potency and selectivity.
• Developed compound 93 (SR-318) through a combinatorial approach.
• SR-318 demonstrated excellent potency and selectivity for p38α/β and inhibited TNF-α release.

Conclusions:

• SR-318 is a potent and selective type-II inhibitor of p38α/β.
• The compound targets a unique inactive kinase conformation.
• SR-318 serves as a valuable chemical probe for investigating p38α/β isoforms.