Title:Preclinical Studies of PROTACs in Hematological Malignancies
Volume: 21
Issue: 1
Author(s): Ota Fuchs*Radka Bokorova
Affiliation:
- Department of Genomics, Institute of Hematology and Blood Transfusion, Prague,Czech Republic
Keywords:
Proteolysis targeting chimera, ubiquitin-proteasome system, E3 ubiquitin ligase, cereblon, von hippel lindau,
cellular inhibitor of apoptosis 1, leukemia, lymphoma.
Abstract: Incorrectly expressed or mutated proteins associated with hematologic malignancies
have been generally targeted by chemotherapy using small-molecule inhibitors or monoclonal antibodies.
But the majority of these intracellular proteins are without active sites and antigens. PROTACs,
proteolysis targeting chimeras, are bifunctional molecules designed to polyubiquitinate and
degrade specific pathological proteins of interest (POIs) by hijacking the activity of E3-ubiquitin ligases
for POI polyubiquitination and subsequent degradation by the proteasome. This strategy utilizes
the ubiquitin-proteasome system for the degradation of specific proteins in the cell. In many
cases, including hematologic malignancies, inducing protein degradation as a therapeutic strategy
offers therapeutic benefits over classical enzyme inhibition connected with resistance to inhibitors.
Limitations of small-molecule inhibitors are shown. PROTACs can polyubiquitinate and mark for
degradation of “undruggable“proteins, e.g. transcription factor STAT3 and scaffold proteins. Today,
this technology is used in preclinical studies in various hematologic malignancies, mainly for
targeting drug-resistant bromodomain and extraterminal proteins and Bruton tyrosine kinase. Several
mechanisms limiting selectivity and safety of PROTAC molecules function are also discussed.
