Catalytic in vivo protein knockdown by small-molecule PROTACs
By Daniel P. Bondeson, A. Mareș, I. E. Smith, Eunhwa Ko, Sebastien Campos, Afjal H Miah, K. Mulholland, Natasha Routly, Dennis L. Buckley, J. Gustafson and 19 more. Nature Chemical Biology, 2015
1,106 citations recorded by the source corpus.
The current predominant theapeutic paradigm is based on maximizing drug-receptor occupancy to achieve clinical benefit. This strategy, however, generally requires excessive drug concentrations to ensure sufficient occupancy, often leading to adverse side effects. Here, we describe major improvements to the proteolysis targeting chimeras (PROTACs) method, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target’s ubiquitination and degradation. These compounds behave catalytically in their ability to induce the ubiquitination of super-stoichiometric quantities of proteins, providing efficacy that is not limited by equilibrium occupancy. We present two PROTACs that are capable of specifically reducing protein levels by >90% at nanomolar concentrations. In addition, mouse studies indicate that they provide broad tissue distribution and knockdown of the targeted protein in tumor xenografts. Together, these data demonstrate a protein knockdown system combining many of the favorable properties of small-molecule agents with the potent protein knockdown of RNAi and CRISPR.
Subfields: Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/65a23df4dfbdd0fb31e5c120749a8757e6028407
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Citations in the corpus
- Lessons in PROTAC design from selective degradation with a promiscuous warhead (2017, background): “Importantly, both ligases are able to degrade cytosolic (RIPK2 and p38d), membrane-bound (c-Met and other RTKs, see Burslem et al., 2017), and nuclear proteins (ERRa and IKZF1), indicating that within these cellular subcompartments both ligases have equivalent access to potential PROTAC targets.”
- PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer (2016, background): “These heterobifunctional molecules, known as “proteolysis targeting chimeras” (PROTACs), contain a ligand for a target protein of interest connected via a linker to a ligand for an E3 ubiquitin ligase (26, 27).”
- Proteolysis Targeting Chimeras as Therapeutics and Tools for Biological Discovery (2020, positive): “…Validation Once a PROTAC is identified, it is crucial to carefully characterize the degradation event via control experiments -- e.g., via qPCR confirmation that protein loss occurs at a posttranslational level and not by decreases in mRNA (Bondeson et al., 2015) -- prior to its use as a tool.”