Targeted protein degradation (TPD) is a novel drug discovery strategy
that eradicates aberrant proteins from cells by hijacking the
intracellular degradation pathway with small heterobifunctional
molecules such as PROteolysis TArgeting Chimeras (PROTACs)
(Figure 1).
2 TPD can overcome many of the limitations of traditional
inhibitors, such as targeting non-functional sites on the protein of
interest (POI) and the ability to overcome resistance mechanisms.
3
Therefore, TPD has the potential to expand the druggable proteome
and offer treatment for various diseases in such therapeutic areas as
cancer, inflammation and neurodegeneration.
2 Central to TPD is the
formation of a ternary complex (POI:degrader:E3 Ligase) which brings
the POI into contact with the E3 ligase, essential for ubiquitination to
occur
PROTACs – From Rational Design and Synthesis to Biophysical Assessment: A Case Study Based on BRPF1b
