PROTAC�ing oncoproteins: targeted protein degradation for cancer therapy
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Date
2023-03-30T00:00:00
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Publisher
BioMed Central Ltd
Abstract
Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these therapies is often related to adaptive changes in the target oncoprotein which reduce binding affinity. The arsenal of targeted cancer therapies, moreover, lacks coverage of several notorious oncoproteins with challenging features for inhibitor development. Degraders are a relatively new therapeutic modality which deplete the target protein by hijacking the cellular protein destruction machinery. Degraders offer several advantages for cancer therapy including resiliency to acquired mutations in the target protein, enhanced selectivity, lower dosing requirements, and the potential to abrogate oncogenic transcription factors and scaffolding proteins. Herein, we review the development of proteolysis targeting chimeras (PROTACs) for selected cancer therapy targets and their reported biological activities. The medicinal chemistry of PROTAC design has been a challenging area of active research, but the recent advances in the field will usher in an era of rational degrader design. � 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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Keywords
Humans, Neoplasms, Oncogene Proteins, Proteolysis, Transcription Factors, Ubiquitin-Protein Ligases, Abelson kinase, anaplastic lymphoma kinase, breakpoint cluster region protein, BRG1 protein, BRM protein, Bruton tyrosine kinase, CD135 antigen, cyclin dependent kinase 9, epidermal growth factor receptor, estrogen, estrogen related receptor alpha, focal adhesion kinase, interleukin 1 receptor associated kinase 4, K ras protein, nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1, oncoprotein, proteasome, protein bcl xl, protein tyrosine phosphatase SHP 2, proteolysis targeting chimera, STAT3 protein, ubiquitin, oncoprotein, transcription factor, ubiquitin protein ligase, biological activity, cancer therapy, drug design, drug development, human, medicinal chemistry, nonhuman, protein degradation, Review, genetics, metabolism, neoplasm, protein degradation