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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Solution Conformations Shed Light on PROTAC Cell Permeability.
Yoseph Atilaw,Vasanthanathan Poongavanam,Caroline Svensson Nilsson,Duy Nguyen,Anja Giese,Daniel Meibom,Máté Erdélyi,Jan Kihlberg +7 more
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The emerging role of mass spectrometry-based proteomics in drug discovery
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Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells
Daniel M. Foulkes,Dominic P. Byrne,Wayland Yeung,Safal Shrestha,Fiona P. Bailey,Samantha Ferries,Claire E. Eyers,Karen Keeshan,Carrow I. Wells,David H. Drewry,William J. Zuercher,Natarajan Kannan,Patrick A. Eyers +12 more
TL;DR: It is found that TRIB2 is a target of previously described small-molecule protein kinase inhibitors, which were originally designed to inhibit the canonical kinase domains of epidermal growth factor receptor tyrosine kinase family members.
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Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications
Trevor J. Hughes,Jian Su +1 more
TL;DR: In this article , a cysteine-reactive covalent ligand, EN106, was used as a recruiter for FEM1B, an E3 ligase recently discovered as the critical component of the cellular response to reductive stress.
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Phthalimide conjugations for the degradation of oncogenic PI3K.
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