No major scientific breakthrough comes without its challenges. This is certainly true of targeted protein degraders (TPDs), which have rapidly become one of the most dynamic areas within oral solid dose drug development.

The idea behind TPDs, encompassing both proteolysis-targeting chimeras (PROTACs) and molecular glues, emerged in the early 2000s as a novel means of removing, rather than merely inhibiting, disease-causing proteins. The first PROTACs, described in 2001 by the Crews and Deshaies laboratories, used peptide linkers to connect a target ligand with an E3 ubiquitin ligase ligand, ultimately directing the target protein for degradation. While conceptually elegant, these early molecules were large, unstable and lacked permeability, making them unsuitable as therapies. Molecular glues had a precedent in drugs such as thalidomide, but their discovery was largely serendipitous and their mechanisms poorly defined.

For years, TPD research remained largely confined to academic settings, constrained by limited availability of E3 ligases, the absence of predictive models for ternary complex formation, synthetic difficulties and the prevailing view that molecules of such size could never be orally bioavailable. Over the last decade, however, advances in structural biology, computational modelling, small-molecule chemistry and clinical validation have shifted this perspective. The central challenge is no longer whether TPDs can function, but how to deliver these inherently bulky and poorly soluble molecules in a form that the body can effectively absorb.