The Mechanism of Ubiquitin Ligase in Protein Degradation

Molecular glue compounds induce protein–protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation. These molecular glue degraders, unlike typical enzyme inhibitors, function sub-stoichiometrically to catalyze the fast depletion of previously inaccessible targets. This eliminates the need for a substrate receptor and allows the cyclin to be ubiquitinated and degraded. Cyclin subunits must interact with cyclin dependent kinases subunits to be active, and when specific cyclins are stimulated, they oscillate in the cell cycle in various ways. When the compound attaches to the cyclin dependent kinase (CDK) it induces an E3 Ligase to be recruited. A complex between CDK-cyclin and an adaptor protein termed DDB1 forms because of the CDK inhibitor. Once the kinase has been degraded, the developed compound can rebind to a new kinase to repeat the degradation process with the help of enzymes. To make this compound a solution 4-amino benzyl cyanide was added drop wise to a solution of cyanuric chloride. Then thin-layer chromatography, purification, and Nuclear Magnetic Resonance was performed after each reaction to confirm the product's functional groups.