Journal ArticleDOI
The rise of covalent proteolysis targeting chimeras.
Ronen Gabizon,Nir London +1 more
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TLDR
A recent review of the recent progress in the emerging field of covalent PROTACs can be found in this paper, where the authors review the recent developments in this field.About:
This article is published in Current Opinion in Chemical Biology.The article was published on 2021-02-04. It has received 42 citations till now. The article focuses on the topics: Protein degradation.read more
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Journal ArticleDOI
PROTACs: past, present and future.
Ke Li,Craig M. Crews +1 more
TL;DR: Important milestones are highlighted and lessons learned about targeted protein degradation (TPD) in recent years are discussed and conjecture on the efforts still needed to expand the toolbox for PROTAC discovery to ultimately provide promising therapeutics are conjecture.
Journal ArticleDOI
PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)
TL;DR: Proteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years as discussed by the authors , which uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through a ubiquitin-proteasome system.
Journal ArticleDOI
E3 ligase ligand chemistries: from building blocks to protein degraders.
TL;DR: A comprehensive review of liganded E3 ligases, their chemistries, appropriate derivatisation, and synthetic approaches towards their incorporation into heterobifunctional degraders can serve as a chemistry blueprint for PROTAC researchers during their future ventures into the complex field of targeted protein degradation.
Journal ArticleDOI
Chemistries of bifunctional PROTAC degraders.
TL;DR: This review highlights the important advances in this rapidly growing field and critical limitations of the traditional trial-and-error approach to developing PROTACs by analyzing numerous representative examples of Protolysis targeting chimeras development.
Journal ArticleDOI
Clinical considerations for the design of PROTACs in cancer
TL;DR: In this article , the authors reviewed the current development stage of PROTACs in cancer to categorize the best PROTAC construction and showed that most ligases evaluated were not highly present in tumors except for MDM2 in breast, lung, prostate and gastric cancer.
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Journal ArticleDOI
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
TL;DR: The development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C) and structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner are provided.
Journal ArticleDOI
Quantitative reactivity profiling predicts functional cysteines in proteomes
Eranthie Weerapana,Chu Wang,Gabriel M. Simon,Florian Richter,Sagar D. Khare,Myles B. D. Dillon,Daniel A. Bachovchin,Kerri A. Mowen,David Baker,Benjamin F. Cravatt +9 more
TL;DR: It is demonstrated that quantitative reactivity profiling can form the basis for screening and functional assignment of cysteines in computationally designed proteins, where it discriminated catalytically active from inactive cysteine hydrolase designs.
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Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.
Kathleen M. Sakamoto,Kyung Bo Kim,Akiko Kumagai,Frank Mercurio,Craig M. Crews,Raymond J. Deshaies +5 more
TL;DR: It is shown that MetAP-2 can be tethered to SCFβ-TRCP, ubiquitinated, and degraded in a Protac-1-dependent manner, which may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.
Journal ArticleDOI
Catalytic in vivo protein knockdown by small-molecule PROTACs
Daniel P. Bondeson,Alina Mares,Ian Edward David Smith,Ko Eunhwa,Sebastien Andre Campos,Afjal Hussain Miah,Katie E Mulholland,Natasha Routly,Dennis L. Buckley,Jeffrey L. Gustafson,Nico Zinn,Paola Grandi,Satoko Shimamura,Giovanna Bergamini,Maria Faelth-Savitski,Marcus Bantscheff,Carly S. Cox,Deborah A. Gordon,Ryan R. Willard,John J. Flanagan,Linda N. Casillas,Bartholomew J. Votta,Willem den Besten,Kristoffer Famm,Laurens Kruidenier,Paul S. Carter,John D. Harling,Ian Churcher,Craig M. Crews +28 more
TL;DR: Major improvements to the proteolysis targeting chimeras (PROTACs) method are described, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target's ubiquitination and degradation.
Journal ArticleDOI
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Jing Lu,Yimin Qian,Martha Altieri,Hanqing Dong,Jing Wang,Kanak Raina,John Hines,James D. Winkler,Andrew P. Crew,Kevin Coleman,Craig M. Crews +10 more
TL;DR: ARV-825 is designed, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation ofBRD4 in all BL cell lines tested.