PROTACs – From Rational Design and Synthesis to Biophysical Assessment: A Case Study Based on BRPF1b

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.
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

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