Enabling Protein Degradation Drug Discovery

PROTACs and Molecular Glues

The ubiquitin proteasome system (UPS) is the cell’s principle pathway for controlling regulated protein turnover and consists of a series of enzymes which conjugate ubiquitin chains to a target protein (E1 activating enzymes, E2 conjugating enzymes and E3 ligases) – in an event known as polyubiquitylation – and a series of enzymes which deconjugate ubiquitin chains (deubiquitylases; DUBs) – see here for further details.  Certain types of polyubiquitin chains conjugated to a protein by the UPS can direct that protein to be degraded by the cellular proteasome complex.

PROteolysis Targeting Chimeras (PROTACs) and molecular glues provide an approach for the targeted degradation of a protein of interest (POI) with a small molecule; a modality described as one that can address the “undruggable” proteome.  PROTACs and related molecule glue molecules hijack the UPS to enable “on demand” degradation of the POI.

A PROTAC is a heterobifunctional molecule consisting of ligand that engages the POI to be degraded and one that binds an E3 ligase or an E3 ligase substrate binding adaptor.  The two elements are joined by a linker molecule.  Upon engagement of the POI with the E3 ligase complex to form a ternary complex the POI may be polyubiquitylated if it is appropriately positioned relative to the E3 ligase complex.  The POI is then degraded by the proteasome complex.  Since the PROTAC can be recycled to repeat this process it is therefore “event driven” with the PROTAC having a catalytic mechanism of action (MOA).

Molecular glues are PROTAC related molecules that display low binding affinities for either the E3 ligase or the POI but enhance such protein-protein interactions enabling engagement of the POI with the E3 ligase and subsequent polyubiquitylation and degradation of the POI.  Like PROTACs, molecular glues display an event driven catalytic MOA.