2
A P P L I C A T I O N N O T E
...AND THE CURRENT STATUS QUO
The emerging field of proximity-inducing drugs holds significant promise for advancing therapeutic
development. This modality brings two proteins into close proximity, triggering a variety of biological
events such as targeted protein degradation, inhibition of protein interactions (PPIs), altering protein
location, or enhancing phosphorylation. PROTACs, the most well-known proximity inducers, have
binding moieties for both a target protein and an E3 ligase, and function by promoting ubiquitination
and subsequent degradation of the target. They have already been shown to facilitate degradation
of targets previously thought to be "undruggable" — like transcription factors.
Due to their modular structure, PROTACs are relatively simple to design and optimize. However,
in complex biological systems, they face several challenges due to their molecular weight and
lipophilicity. These larger molecules o en suffer from poor bioavailability, higher toxicity, and off-
target effects. Depending on the involved ligase and the disease context, there is also a danger
of mechanism-related toxicity. Molecular glues on the other hand are typically smaller and can
overcome those limitations. However, finding and optimizing molecules with glue-like properties
is significantly more difficult. A key feature of molecular glues is cooperativity: the extent to which
the target affinity of the molecular glue is increased by the presence of a chaperone protein. In this
user experience case study, Dr. Hans-Jörg Roth, retired Director of Global Discovery Chemistry at
Novartis, discusses how optimizing cooperativity can allow for the development of smaller, more
efficient molecules with higher selectivity and a better safety profile.
Proximity Inducers
Figure 1. Ubiquitin: A Central Regulator in PROTAC-Mediated Protein Degradation.
U S E R C A S E S T U D Y
