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 Substituted Phenyl Dihydrouracil as the Novel Achiral Cereblon Ligands for Targeted Protein Degradation.
TL;DR: In this article , substituted achiral phenyl dihydrouracil (PDHU) was used as a novel class of CRBN ligands for the development of PROTACs.
Book ChapterDOI
Synthesis, Biochemical, and Cellular Evaluation of HDAC6 Targeting Proteolysis Targeting Chimeras.
Salma Az Darwish,Tino Heimburg,Johannes Ridinger,Daniel Herp,Matthias Schmidt,Christophe Romier,Manfred Jung,Ina Oehme,Wolfgang Sippl +8 more
TL;DR: In this article , the synthesis of histone deacetylase 6 (HDAC6) targeting PROTACs based on previously synthesized benzohydroxamates selectively inhibiting HDAC6 and how to assess their activities in different biochemical in vitro assays and in cellular assays.
Journal ArticleDOI
Genetic manipulation and targeted protein degradation in mammalian systems: practical considerations, tips and tricks for discovery research
TL;DR: A short review of gene perturbation in mammalian cells and how editing and differentiation of pluripotent stem cells can complement more traditional approaches can be found in this article , where the authors introduce novel targeted protein degradation approaches as an alternative to DNA/RNA-based manipulation.
Journal ArticleDOI
[Research Progress of Proteolysis Targeting Chimeria in NSCLC Therapy].
TL;DR: Proteolysis targeting chimeria drugs with their unique event-driven advantages, are expected to overcome acquired drug resistance caused by small molecule inhibitors and show good therapeutic potential for undruggable targets, thereby providing a new strategy for the treatment of NSCLC.
Posted ContentDOI
Pooled CRISPR screening of high-content cellular phenotypes by ghost cytometry
Asako Tsubouchi,Yuri An,Yoko Kawamura,Yuichi Yanagihashi,Yuri Murata,Kazuki Teranishi,Soh Ishiguro,Hiroyuki Aburatani,Nozomu Yachie,Sadao Ota +9 more
TL;DR: In this paper , a machine vision-based cell sorter enabled genome-wide perturbation screens for high-content cell phenotypes even without labeling even without invasive staining.
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