Targeting the DFG-in kinase conformation: a new trend emerging from a patent analysis

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Aberrant kinase signaling drives numerous diseases.
• Kinase inhibitors like imatinib and dasatinib are successful treatments for hematological malignancies.
• There is growing interest in kinases as therapeutic targets, shown by increased patent and publication activity.

Purpose of the Study:

• To review recent patents on small molecules targeting the DFG-in active kinase conformation.
• To discuss 'Type I½' inhibitors against targets including B-Raf, p38α, Jak2, and EphB4.
• To highlight preclinical and clinical data for promising new molecular entities.

Main Methods:

• Patent literature review focusing on small molecule kinase inhibitors.
• Analysis of inhibitors targeting the DFG-in active conformation ('Type I½' inhibitors).
• Review of preclinical and clinical data for selected drug candidates.

Main Results:

• Recent patents describe novel small molecules targeting the DFG-in kinase conformation.
• These inhibitors are directed against clinically relevant kinases such as B-Raf, p38α, Jak2, and EphB4.
• Promising preclinical and clinical data exist for several new molecular entities.

Conclusions:

• Small molecules targeting the DFG-in kinase conformation represent a significant area of drug discovery.
• 'Type I½' inhibitors offer a promising strategy for developing new therapeutics.
• Further clinical development is warranted for the highlighted molecular entities.