Comprehensive characterization of the Published Kinase Inhibitor Set

Area of Science:

• Biochemistry
• Pharmacology
• Chemical Biology

Background:

• Protein kinase inhibitors are successful therapeutics, yet research targets only a fraction of kinases.
• The Published Kinase Inhibitor Set (PKIS) was released to broaden kinase research and validate targets via open-source methods.

Purpose of the Study:

• To comprehensively characterize the PKIS, a collection of 367 small-molecule kinase inhibitors.
• To identify novel chemical starting points for probes targeting previously uncharacterized kinases.
• To explore the utility of PKIS compounds in cellular assays for cancer and angiogenesis.

Main Methods:

• Screening the PKIS against 224 recombinant kinases and 24 G protein-coupled receptors.
• Utilizing cellular assays to assess cancer cell proliferation and angiogenesis.
• Developing selective inhibitors for LOK and SLK kinases based on PKIS leads.

Main Results:

• Identification of chemical starting points for orphan kinase probe development.
• Successful development of a selective inhibitor for the previously untargeted LOK and SLK kinases.
• Discovery of compounds modulating cancer cell growth and angiogenesis in vitro.

Conclusions:

• The PKIS provides valuable reagents and data for advancing research on the kinome.
• This open-source approach facilitates the discovery of inhibitors for historically untargeted kinases.
• The study demonstrates an efficient strategy for expanding the chemical toolkit for kinase research.