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
Citations
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Journal ArticleDOI
A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL
Bingqi Tong,Jessica N. Spradlin,Luiz F. T. Novaes,Erika Zhang,Xirui Hu,Malte Moeller,Scott M. Brittain,Scott M. Brittain,Lynn M. McGregor,Lynn M. McGregor,Jeffrey Mckenna,Jeffrey Mckenna,John A. Tallarico,John A. Tallarico,Markus Schirle,Markus Schirle,Thomas J. Maimone,Daniel K. Nomura +17 more
TL;DR: Nimbolide is established as an additional general E3 ligase recruiter for PROTACs, and the importance of expanding upon the arsenal of E 3 ligase recruiters is demonstrated, as such molecules confer differing selectivity for the degradation of neo-substrate proteins.
Journal ArticleDOI
Development of Selective Histone Deacetylase 6 (HDAC6) Degraders Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase
Ka Yang,Hao Wu,Zhongrui Zhang,Eric D Leisten,Xueqing Nie,Binkai Liu,Zhi Wen,Jing Zhang,Michael D Cunningham,Weiping Tang +9 more
TL;DR: The first cell-permeable HDAC6-selective degraders employing Von Hippel-Lindau (VHL) E3 ubiquitin ligase, which does not have any known neo-substrates are reported.
Journal ArticleDOI
A caged E3 ligase ligand for PROTAC-mediated protein degradation with light
Cyrille S Kounde,Maria M. Shchepinova,Charlie N Saunders,Marcel Muelbaier,Mark David Rackham,John D. Harling,Edward W. Tate +6 more
TL;DR: A light-activated degrader was designed by photocaging an essential E3 ligase binding motif in a BRD4 targeting PROTAC to achieve greater spatiotemporal control of PROTAC-induced protein degradation.
Journal ArticleDOI
Recent Developments in PROTAC-Mediated Protein Degradation: From Bench to Clinic
Zhenyi Hu,Craig M. Crews +1 more
TL;DR: Proteolysis-targeting chimeras (PROTACs), an emerging paradigm-shifting technology, hijacks the ubiquitin-proteasome system for targeted protein degradation.
Journal ArticleDOI
Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC).
Hao Zhang,Hong-Yi Zhao,Xiao-Xiao Xi,Yan-Jie Liu,Minhang Xin,Shuai Mao,Jun-Jie Zhang,A-Xin Lu,San-Qi Zhang +8 more
TL;DR: The discovery of small molecule EGFR degraders based on the proteolysis targeting chimera (PROTAC) strategy demonstrated that compounds 2 and 10 could serve as effective EGFRdel19-targeting degrader in HCC827 cells.
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