Induced protein degradation: an emerging drug discovery paradigm
Ashton C. Lai,Craig M. Crews +1 more
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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
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Structural basis of PROTAC cooperative recognition for selective protein degradation.
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References
More filters
Journal ArticleDOI
Tamoxifen for early breast cancer: An overview of the randomised trials
TL;DR: The absolute improvement in recurrence was greater during the first 5 years, whereas the improvement in survival grew steadily larger throughout the first 10 years, and these benefits appeared to be largely irrespective of age, menopausal status, daily tamoxifen dose, and of whether chemotherapy had been given to both groups.
Journal Article
Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group
TL;DR: There have been many randomised trials of adjuvant tamoxifen among women with early breast cancer, and an updated overview of their results is presented in this paper, which approximately doubles the amount of evidence from trials of about 5 years of tamoxifier and, taking all trials together, on events occurring more than 5 years after randomisation.
Journal ArticleDOI
Analysis of nanoparticle delivery to tumours
Stefan Wilhelm,Anthony J. Tavares,Qin Dai,Seiichi Ohta,Seiichi Ohta,Julie Audet,Harold F. Dvorak,Warren C. W. Chan +7 more
TL;DR: This Perspective explores and explains the fundamental dogma of nanoparticle delivery to tumours and answers two central questions: ‘ how many nanoparticles accumulate in a tumour?’ and ‘how does this number affect the clinical translation of nanomedicines?'
Journal ArticleDOI
How many drug targets are there
TL;DR: A consensus number of current drug targets for all classes of approved therapeutic drugs is proposed, and an emerging realization of the importance of polypharmacology and also the power of a gene-family-led approach in generating novel and important therapies is highlighted.
Development and Applications of CRISPR-Cas9 for Genome Engineering
TL;DR: The development and applications of Cas9 are described for a variety of research or translational applications while highlighting challenges as well as future directions.
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