Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome

Area of Science:

• Biochemistry
• Chemical Biology
• Drug Discovery

Background:

• Covalent kinase inhibitors targeting cysteine residues are clinically significant.
• While 215 kinases have potential cysteine sites, only 40 are currently targeted, with limited cysteine site focus.

Purpose of the Study:

• To develop a strategy for identifying novel targetable cysteines on kinases.
• To expand the scope of covalent kinase inhibitor development.

Main Methods:

• Utilized a multi-targeted acrylamide-modified inhibitor (SM1-71).
• Employed complementary chemoproteomic and cellular approaches.
• Identified targetable cysteines across multiple kinase families.

Main Results:

• Successfully identified 23 kinases amenable to covalent inhibition with SM1-71.
• Included kinases such as MKNK2, MAP2K family, GSK3A/B, MAPK1/3, SRC, and FGFR1.
• Discovered nine kinases not previously targeted by covalent inhibitors.

Conclusions:

• The study expands the landscape of targetable kinases for covalent inhibition.
• Highlights significant opportunities for developing new covalent kinase inhibitors.
• Demonstrates the utility of a multi-targeted inhibitor approach in chemoproteomics.