3
A P P L I C A T I O N N O T E
ADDRESSING THE CHALLENGE OF LIMITED CHAPERONE LIBRARIES
One of the major challenges in screening for molecular glues is the limitation of chaperone
1
focused
libraries. Hans-Jörg states, "Building large chaperone-focused libraries is very expensive and
synthetically challenging." The difficulty arises from maintaining both the required affinity to the
chaperone and the chemical diversity needed for recruitment of different and diverse targets. Hans-
Jörg highlights that current approaches, which rely heavily on a few well-known chaperones like
FKBP12, Cyclophilin, CBRN and VHL, limit the range of potential targets, restricting the potential of
drug discovery efforts.
A SHIFT TOWARD CHAPERONE-AGNOSTIC SCREENING
Rather than continuing to expand these chaperone libraries, Hans-Jörg believes that a more promising
direction is to develop chaperone-agnostic screening methods. "I see the chaperone agnostic approach
as more viable, especially for addressing difficult targets, where the only way of modulating them is their
involvement in a ternary complex," he says. Over time, more chaperones are expected to emerge in the
literature, providing researchers with the flexibility to choose the most appropriate chaperones for the
modulation of the envisaged target with respect to abundance and cellular/tissue location. This shi
would lead to mechanism-related accumulation of the drug compound in the desired tissues and cells,
and therefore to higher selectivity and better safety profiles. Hans-Jörg's perspective emphasizes the
potential for a broader and more adaptable approach, moving away from the limitations of chaperone-
specific screening while maintaining the advantages of molecular glues over bi-functional proximity
inducers.
1
The term chaperone refers to proteins that, when brought into complex with the disease-relevant protein-of-interest,
facilitate its modulation.
U S E R C A S E S T U D Y
