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
Frontiers in Medicinal Chemistry 2017 in Bern, Switzerland.
TL;DR: The 2017 Frontiers in Medicinal Chemistry (FiMC) conference, organized jointly by the German Chemical Society, the German Pharmaceutical Society, and the Swiss chemical Society, was held at the Department of Chemistry and Biochemistry of the University of Bern in February 2017.
Journal ArticleDOI
Selective degradation of cellular BRD3 and BRD4-L promoted by PROTAC molecules in six cancer cell lines.
Ziqin Yan,Xilin Lyu,Dongze Lin,Gaoxing Wu,Yang Gong,Xuelian Ren,Jian Xiao,Jian-Feng Lou,He Huang,Yi Chen,Yujun Zhao +10 more
TL;DR: In this article , a novel PROTAC molecule was proposed that promoted selective degradation of cellular BRD3 and BRD4-L, but not BRD2 or BRD 4-S, in a panel of six cancer cell lines.
Journal ArticleDOI
Genetically-encoded degraders as versatile modulators of intracellular therapeutic targets
TL;DR: A review of the progress of genetic-encoded targeted protein degradation (TPD) can be found in this paper , which highlights innovative technologies that have the potential to advance the development of GE-TPDD.
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Engineering ligand stabilized aquaporin reporters for magnetic resonance imaging
TL;DR: LSAqp1 as mentioned in this paper is a fusion protein composed of aquaporin-1 and a degradation tag that is sensitive to a cell-permeable ligand, which allows for dynamic small molecule modulation of MRI signals.
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