Covalent inhibition of cyclin dependent kinase 2 (CDK2) through modification of a non-catalytic lysine side chain

• Online Access: http://hdl.handle.net/2047/D20317957

Covalent Inhibitors have been used as drugs, such as aspirin. Boronic acid aldehyde warheads have been successfully used to covalently bind to lysine residues in Myeloid cell leukemia 1 (MCL-1). The covalent inhibition of MCL-1 prevents an anti-apoptosis signal. Given the success with using boronic acid carbonyls in MCL-1, we decided to apply this covalent inhibition warhead approach for CDK2 inhibition. This approach builds upon the previously discovered inhibition of NU6300 which was designed to target the lysine (K89) amino acid as an irreversible covalent inhibitor of CDK2. Four compounds resulted from this design as potential targets for synthesis and study. While we successfully synthesized three out of the four compounds, the key boronic acid carbonyl was not made. The synthesis accomplished so far suggest that boronic carbonyls can be eventually prepared by the route developed.