Drug discovery: First rational strategy to find molecular glue degraders


Date:
August 3, 2020
Source:
CeMM Research Center for Molecular Medicine of the Austrian Academy
of Sciences
Summary:
Targeted protein degradation (TPD) represents a novel paradigm
in drug discovery that could lead to more efficient medicines
to treat diseases such as cancer. 'Molecular glue degrader'are
an emerging but understudied class of small molecules that have
been shown to induce degradation of proteins commonly considered
'undruggable'. Researchers have described a strategy that, for the
first time, enables the rational and highly scalable discovery of
novel molecular glue degraders.



FULL STORY ========================================================================== Despite enormous efforts to advance traditional pharmacology
approaches, more than three quarters of all human proteins remain
beyond the reach of therapeutic development. Targeted protein
degradation (TPD) is a novel approach that could overcome this
and other limitations, and thus represents a promising therapeutic
strategy. TPD is based on small molecules, generally called"degraders,"
which can eliminate disease-causing proteins by causing their
destabilization. Mechanistically, these degrader drugs repurpose the
cellular protein quality control system, tweaking it to recognize and
eliminate harmful proteins. In detail, they re-direct members of the
protein family of E3 ubiquitin ligases (E3s) towards the disease-causing
target protein. This leads to a "molecular earmarking" of the harmful
protein via a process called "ubiquitination." Subsequently, the
ubiquitinated protein is recognized and degraded by the molecular
machine called the proteasome, which serves as the cellular garbage
disposal system.


==========================================================================
In this study, CeMM researchers turned their focus to a subset
of degraders called "molecular glue degraders." This class of
seemingly rare small molecules that has been shown to induce the
degradation of target proteins that could not be blocked via ways of traditional pharmacology. Consequently, these proteins had been termed "undruggable." The best characterized examples are the clinically approved thalidomide analogs, effective for the treatment of different blood
cancers. Unfortunately, the discovery of the few described molecular glue degraders has historically been a process entirely driven by serendipity
and no rational discovery strategies existed.

To overcome this limitation, Georg Winter's group at CeMM set out to
innovate a scalable strategy towards the discovery of novel molecular
glue degraders via phenotypic chemical screening. To this end, first
author and CeMM postdoctoral fellow Cristina Mayor-Ruiz and colleagues engineered cellular systems widely impaired in E3 activity. Differential viability between these models and E3- proficient cells was used to
identify compounds that depend on active E3s, and therefore, potential molecular glue degraders. Researchers integrated functional genomics
with proteomics and drug-interaction strategies, to characterize the
most promising compounds. They validated the approach by discovering
a new RBM39 molecular glue degrader, structurally similar to others
previously described. Importantly, they discovered a set of novel
molecular glues that induce the degradation of the protein cyclin K,
known to be essential in many different cancer types. Interestingly,
these novel cyclin K degraders function via an unprecedented molecular mechanism of action that involves the E3 CUL4B:DDB1 and that has never
been therapeutically explored before.

This study, performed in close collaboration with CeMM PI Stefan
Kubicek, thus provides the first framework towards the discovery of
molecular glue degraders that can be highly scaled, but also strongly diversified. "I truly believe that we are only scratching the surface of possibilities. This study is chapter one of many chapters to follow. We
will see a revolution in the way researchers perceive and execute
therapeutic strategies for previously incurable diseases by crafting glue degrader strategies that will enable them to eliminate therapeutic targets
that could not be explored with traditional pharmacologic approaches,"
says CeMM PI and last author of the study Georg Winter.


========================================================================== Story Source: Materials provided by CeMM_Research_Center_for_Molecular_Medicine_of_the Austrian_Academy_of_Sciences. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Mayor-Ruiz, C., Bauer, S., Brand, M. et al. Rational discovery of
molecular glue degraders via scalable chemical profiling. Nat Chem
Biol, 2020 DOI: 10.1038/s41589-020-0594-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200803120128.htm

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