PROTACs- a game-changing technology.
Markella Konstantinidou,Jingyao Li,Bidong Zhang,Zefeng Wang,Shabnam Shaabani,Frans ter Brake,Khaled Essa,Alexander Dömling +7 more
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TLDR
PROTACs have shown remarkable biological responses in challenging targets, including an unprecedented selectivity over protein family members and even efficacy starting from weak or unspecific binders, and are expected to soon become a new therapeutic category of drugs.Abstract:
Introduction: Proteolysis - targeting chimeras (PROTACs) have emerged as a new modality with the potential to revolutionize drug discovery. PROTACs are heterobifunctional molecules comprising of a ligand targeting a protein of interest, a ligand targeting an E3 ligase and a connecting linker. The aim is instead of inhibiting the target to induce its proteasomal degradation. Areas covered: PROTACs, due to their bifunctional design, possess properties that differentiate them from classical inhibitors. A structural analysis, based on published crystal aspects, kinetic features and aspects of selectivity are discussed. Specific types such as homoPROTACs, PROTACs targeting Tau protein and the first PROTACs recently entering clinical trials are examined. Expert opinion: PROTACs have shown remarkable biological responses in challenging targets, including an unprecedented selectivity over protein family members and even efficacy starting from weak or unspecific binders. Moreover, PROTACs are standing out from classical pharmacology by inducing the degradation of the target protein and not merely its inhibition. However, there are also challenges in the field, such as the rational structure optimization, the evolution of computational tools, limited structural data and the greatly anticipated clinical data. Despite the remaining hurdles, PROTACs are expected to soon become a new therapeutic category of drugs.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.
Journal ArticleDOI
PROTACs: An Emerging Therapeutic Modality in Precision Medicine.
TL;DR: This review highlights the key advantages of PROTACs and then discusses the spatiotemporal regulation of protein degradation, and explores current chemically tractable E3 ligases focusing on expanding the existing repertoire with novel E3ligases to uncover the full potential of TPD.
Journal ArticleDOI
Covalent inhibitors: A rational approach to drug discovery
TL;DR: In this review, a brief historic overview of covalent inhibitors is provided and recent advances focusing on developments in the last decade are summarized.
Journal ArticleDOI
Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel–Lindau (VHL) E3 Ubiquitin Ligase: Structure–Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298)
Pedro Marcos Gomes Soares,M.S. Gadd,Julianty Frost,Carles Galdeano,Lucy Ellis,Ola Epemolu,Sonia Rocha,Kevin D. Read,Alessio Ciulli +8 more
TL;DR: The structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability are reported, leading to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization.
Journal ArticleDOI
Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges.
TL;DR: A detail summary on the latest one year progress of PROTAC target various proteins and elucidate the advantages of PROTac technology are provided.
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Journal ArticleDOI
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.
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