Structural Basis for Targeting the Folded P-Loop Conformation of c-MET

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• The c-MET kinase is a crucial regulator of cellular processes.
• Aberrant c-MET signaling is implicated in various cancers.
• Targeting specific kinase conformations offers a strategy for selective inhibition.

Purpose of the Study:

• To discover novel inhibitors of the c-MET kinase.
• To investigate inhibitors targeting a rare, folded P-loop conformation of c-MET.
• To provide a structural and chemical basis for targeting this conformation.

Main Methods:

• Fragment-based screening against c-MET kinase.
• Structure-activity relationship (SAR) exploration.
• Biochemical and cellular activity assays.
• Kinase selectivity profiling.

Main Results:

• Identification of inhibitors binding to a rare, folded P-loop conformation of c-MET.
• Development of inhibitor 7 with nanomolar biochemical activity against c-MET.
• Demonstration of promising cellular activity and kinase selectivity for inhibitor 7.
• Enhanced structural understanding of the folded P-loop conformation.

Conclusions:

• The study identified novel inhibitors targeting a unique c-MET kinase conformation.
• Inhibitor 7 shows potent activity and selectivity, warranting further development.
• These findings provide a foundation for exploring therapeutically exploitable states of c-MET.