Induced protein degradation: an emerging drug discovery paradigm
Ashton C. Lai,Craig M. Crews +1 more
TLDR
Induced protein degradation has the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.Abstract:
Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination. Emerging technologies based on proteolysis-targeting chimaeras (PROTACs) that exploit cellular quality control machinery to selectively degrade target proteins are attracting considerable attention in the pharmaceutical industry owing to the advantages they could offer over traditional small-molecule strategies. These advantages include the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.read more
Citations
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Journal ArticleDOI
Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer.
Hidetomo Yokoo,Norihito Shibata,Miyako Naganuma,Yuki Murakami,Kiyonaga Fujii,Takahito Ito,Kosuke Aritake,Mikihiko Naito,Yosuke Demizu +8 more
TL;DR: In this article, a chimeric small molecule that degrades prostaglandin D via the ubiquitin-proteasome system, PROTAC(H-PGDS)-1, was developed.
Journal ArticleDOI
Selective Degradation of Target Proteins by Chimeric Small-Molecular Drugs, PROTACs and SNIPERs
TL;DR: This article reviews chimeric drugs that decrease the level of specific proteins such as proteolysis targeting chimeric molecules (PROTACs) and specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs), which target proteins for proteasome-mediated degradation.
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Proteomics in the pharmaceutical and biotechnology industry: a look to the next decade.
TL;DR: Pioneering technologies such as proteomics have helped fuel the biotechnology and pharmaceutical industry with the discovery of novel targets and an intricate understanding of the activity of the RA as discussed by the authors.
Journal ArticleDOI
High-Throughput Quantitative Assay Technologies for Accelerating the Discovery and Optimization of Targeted Protein Degradation Therapeutics:
Jeffrey R Simard,Linda Lee,Ellen F. Vieux,Reina Improgo,Trang N. Tieu,Andrew J. K. Phillips,Stewart L. Fisher,Roy M. Pollock,Eunice Park +8 more
TL;DR: The field of targeted protein degradation is an emerging area for drug discovery in which small molecules are used to recruit E3 ubiquitin ligases to catalyze the ubiquitination and subsequent degradation of disease-causing target proteins by the proteasome in both a dose and time-dependent manner as mentioned in this paper.
Journal ArticleDOI
Induced degradation of protein kinases by bifunctional small molecules: a next-generation strategy
TL;DR: Drug discovery efforts targeting protein kinases should increasingly shift toward generation and screening of inducers of degradation and away from occupancy-based inhibitors of old.
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