Conversion of a PROTAC Mutant Huntingtin Degrader into Small-Molecule Hydrophobic Tags Focusing on Drug-like Properties

The
onset of neurodegenerative disorders (NDs), such as Alzheimer’s
disease, is associated with the accumulation of aggregates of misfolded
proteins. We previously showed that chemical knockdown of ND-related
aggregation-prone proteins can be achieved by proteolysis targeting
chimeras (PROTACs). However, hetero-bifunctional PROTACs generally
show poor permeability into the central nervous system, where NDs
are located. Here, we document the conversion of one of our PROTACs
into hydrophobic tags (HyTs), another class of degraders bearing hydrophobic
degrons. This conversion decreases the molecular weight and the number
of hydrogen bond donors/acceptors. All the developed HyTs lowered
the level of mutant huntingtin, an aggregation-prone protein, with
potency comparable to that of the parent PROTAC. Through IAM chromatography
analysis and in vivo brain penetration assay of the HyTs, we discovered
a brain-permeable HyT. Our results and mechanistic analysis indicate
that conversion of protein degraders into HyTs could be a useful approach
to improve their drug-like properties.