Targeted Protein Degraders – The druggability perspective

TPDs are a class of macromolecular therapeutic compounds that harness the cell’s own protein degradation machinery to selectively break down proteins of interest mainly disease-causing¹. In contrast to non-covalent inhibitors, TPDs offer a broader range of protein targets, including those previously regarded “undruggable” by conventional small molecules². TPDs can be designed to degrade intracellular proteins, membrane proteins, and even transcription factors^2,3.

One of the key advantages of TPDs is their high specificity. They capitalize on the binding affinity between the ligands present in the TPDs and sites present on target protein and the E3 ubiquitin ligase, ensuring precise degradation of the intended protein whilst evading unintended effects on other proteins⁴. Furthermore, compared to classical reversible inhibitors, TPDs exhibit a sustained and long-lasting impact on target protein levels due to their ability to induce protein degradation and removing it altogether⁵. This characteristic is particularly advantageous in chronic diseases where sustained protein suppression is necessary for therapeutic efficacy. TPDs also have the potential to overcome resistance mechanisms commonly observed with non-covalent inhibitors. By promoting protein degradation, instead of solely blocking protein activity, TPDs can bypass mutations or alterations that confer resistance to traditional inhibitors. Moreover, TPDs can be designed to simultaneously degrade multiple target proteins by incorporating multiple ligands into the same bifunctional molecule. This feature presents new possibilities for treating complex diseases involving multiple dysregulated proteins or pathways⁶.

In addition to their protein degradation capability, bifunctional TPDs can modulate protein function as well. These molecules can recruit specific proteins to facilitate protein-protein interactions or alter protein localization, thereby providing additional ways to influence cellular processes⁷.

Since 2001, when the first attempt to synthesize TPD (typical structure in figure 1) was made by Crews and Raymond Deshaies⁸, TPD chemistry and research has come a long way during last two decades.

TPDs made their clinical debut in 2018-19, and presently more than 10 oral and several parenteral TPDs are in Phase I/II clinical trials (Table 1).

Notably, ARV-110 has recently progressed into Phase III. TPDs created niche space of their own driven mainly by their potential to target undruggable proteins. The huge surge in number of pharma companies and institutes pursuing TPD programmes pushing them through preclinical to clinical stage are testimony to the potential of the approach in offering viable solutions for various diseases (Table 2).

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