PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery.
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TLDR
An overview of the main PROTAC‐based approaches that have been developed is provided and the promising opportunities and considerations for the application of this technology in therapies and drug discovery are discussed.Abstract:
Proteolysis-targeting chimeric molecules (PROTACs) represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero-bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate "undruggable" protein targets, such as transcription factors and non-enzymatic proteins, which are not limited to physiological substrates of the ubiquitin-proteasome system. These findings indicate great prospects for PROTACs in the development of therapeutics. However, there are several limitations related to poor stability, biodistribution, and penetrability in vivo. This review provides an overview of the main PROTAC-based approaches that have been developed and discusses the promising opportunities and considerations for the application of this technology in therapies and drug discovery.read more
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PROTACs: great opportunities for academia and industry.
TL;DR: Although PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic.
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The great escape: tumour cell plasticity in resistance to targeted therapy.
TL;DR: The different mechanisms that drive tumour cell plasticity and the potential therapeutic strategies to target them are discussed in order to achieve more durable clinical responses.
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Proteolysis targeting chimeras (PROTACs) in 'beyond rule-of-five' chemical space: Recent progress and future challenges.
TL;DR: This review summarizes and analyzes a representative set of recent PROTACs and highlights some of the potential future challenges facing this promising modality.
Journal ArticleDOI
Targeting the MAPK Pathway in KRAS-Driven Tumors.
TL;DR: Recent efforts to validate individual components of the mitogen-activated protein kinase (MAPK) pathway as targets to treat KRAS-mutant cancers are reviewed by comparing genetic information derived from experimental mouse models ofKRAS-driven lung and pancreatic tumors with the outcome of selective MAPK inhibitors in clinical trials.
Journal ArticleDOI
Degradation of proteins by PROTACs and other strategies.
TL;DR: Recent meaningful research of PROTAC is summarized, including the types of degradation proteins, preliminary biological data in vitro and in vivo, and new E3 ubiquitin ligases, which strongly proved the value of the PROTAC strategy.
References
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Journal ArticleDOI
Multiplex Genome Engineering Using CRISPR/Cas Systems
Le Cong,Le Cong,F. Ann Ran,F. Ann Ran,David M. Cox,David M. Cox,Shuailiang Lin,Shuailiang Lin,Robert P. J. Barretto,Naomi Habib,Patrick D. Hsu,Patrick D. Hsu,Xuebing Wu,Wenyan Jiang,Luciano A. Marraffini,Feng Zhang +15 more
TL;DR: The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage as discussed by the authors.
Multiplex Genome Engineering Using CRISPR/Cas Systems
Le Cong,F. A. Ran,David Benjamin Turitz Cox,Shuailiang Lin,Robert P. J. Barretto,Naomi Habib,Patrick D. Hsu,Xuebing Wu,Wenyan Jiang,Luciano A. Marraffini,Feng Zhang +10 more
TL;DR: Two different type II CRISPR/Cas systems are engineered and it is demonstrated that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.
Journal ArticleDOI
The Ubiquitin System
Avram Hershko,Aaron Ciechanover +1 more
TL;DR: This review discusses recent information on functions and mechanisms of the ubiquitin system and focuses on what the authors know, and would like to know, about the mode of action of ubi...
Journal ArticleDOI
AKT/PKB signaling: navigating downstream.
TL;DR: Those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration are discussed.
Journal ArticleDOI
Targeting of HIF-alpha to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation
Panu Jaakkola,David R. Mole,Ya-Min Tian,Michael I. Wilson,Janine Gielbert,Simon J. Gaskell,Alex von Kriegsheim,Holger F. Hebestreit,Mridul Mukherji,Christopher J. Schofield,Patrick H. Maxwell,Christopher W. Pugh,Peter J. Ratcliffe +12 more
TL;DR: It is shown that the interaction between human pVHL and a specific domain of the HIF-1α subunit is regulated through hydroxylation of a proline residue by an enzyme the authors have termed Hif-α prolyl-hydroxylase (HIF-PH).
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