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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Patent
Tank-binding kinase-1 protacs and associated methods of use
TL;DR: In this paper, a bifunctional compound with E3 ubiquitin ligase binding moiety was proposed to degrade and inhibit TBK 1. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of TBK1.
Journal ArticleDOI
Exploring the PROTAC degron candidates: OBHSA with different side chains as novel selective estrogen receptor degraders (SERDs).
Li Yuanyuan,Silong Zhang,Jing Zhang,Zhiye Hu,Yuan Xiao,Jian Huang,Chune Dong,Shengtang Huang,Hai-Bing Zhou +8 more
TL;DR: New classes of SERDs that contain the OBHSA core structure and different side chains to simply mimic the degrons of proteolysis targeting chimera (PROTAC) and then investigated the structure-activity relationships of these PROTAC-like hybrid compounds, which could effectively inhibit MCF-7 cell proliferation and demonstrated good ERα degradation efficacy.
Journal ArticleDOI
Protein degradation: a validated therapeutic strategy with exciting prospects.
TL;DR: Current strategies for protein degradation with an emphasis on PROTACs and the role of click chemistry in PROTAC research are introduced through the formation of libraries of preclicked PROTacs or in-cell click-formed PROTACS (CLIPTACs).
Journal ArticleDOI
Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC
TL;DR: YF135 as discussed by the authors is a reversible-covalent PROTAC capable of recruiting VHL mediated proteasomal degradation of KRASG12C. YF135 induces the rapid and sustained degradation of endogenous KRASg12C and attenuates pERK signaling in H358 and H23 cells in a reversible manner.
Journal ArticleDOI
Assays and technologies for developing proteolysis targeting chimera degraders.
TL;DR: In this paper, the authors present a comprehensive review of existing techniques for profiling step-by-step along the ubiquitin-proteasome degradation pathway using biochemical and biophysical assays.
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TL;DR: The results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents and the generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.
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