PROTAC technology: A new drug design for chemical biology with many challenges in drug discovery

Guedeney, Nicolas; Cornu, Marie; Schwalen, Florian; Kieffer, Charline; Voisin‐Chiret, Anne Sophie

doi:10.1016/j.drudis.2022.103395

Cited by 43 publications

(51 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Proteolysis-targeting chimeras (PROTACs) are chimeric bifunctional small molecules that recruit an E3 ligase to promote the degradation of a target protein [ 62 ]. Structurally, a typical PROTAC is composed of a ligand capable of binding to an E3 ligase and another ligand that binds to the target protein through a linker.…”

Section: Evolution Of Small-molecule Inhibitors Of Bet Proteinsmentioning

confidence: 99%

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

Xing

Larue

et al. 2023

Molecules

View full text Add to dashboard Cite

The mammalian bromodomain and extra-terminal domain (BET) family of proteins consists of four conserved members (Brd2, Brd3, Brd4, and Brdt) that regulate numerous cancer-related and immunity-associated genes. They are epigenetic readers of histone acetylation with broad specificity. BET proteins are linked to cancer progression due to their interaction with numerous cellular proteins including chromatin-modifying factors, transcription factors, and histone modification enzymes. The spectacular growth in the clinical development of small-molecule BET inhibitors underscores the interest and importance of this protein family as an anticancer target. Current approaches targeting BET proteins for cancer therapy rely on acetylation mimics to block the bromodomains from binding chromatin. However, bromodomain-targeted agents are suffering from dose-limiting toxicities because of their effects on other bromodomain-containing proteins. In this review, we provided an updated summary about the evolution of small-molecule BET inhibitors. The design of bivalent BET inhibitors, kinase and BET dual inhibitors, BET protein proteolysis-targeting chimeras (PROTACs), and Brd4-selective inhibitors are discussed. The novel strategy of targeting the unique C-terminal extra-terminal (ET) domain of BET proteins and its therapeutic significance will also be highlighted. Apart from single agent treatment alone, BET inhibitors have also been combined with other chemotherapeutic modalities for cancer treatment demonstrating favorable clinical outcomes. The investigation of specific biomarkers for predicting the efficacy and resistance of BET inhibitors is needed to fully realize their therapeutic potential in the clinical setting.

show abstract

Section: Evolution Of Small-molecule Inhibitors Of Bet Proteinsmentioning

confidence: 99%

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

Xing

Larue

et al. 2023

Molecules

View full text Add to dashboard Cite

show abstract

“…In vitro evaluated on chemoresistant cancer cell lines by Dr. Poulain’s team, this PROTAC has shown encouraging results. The PROTAC strategy has opened new avenues in terms of drug design and chemical biology; although PROTAC technology has a promising future in drug development, it also has many challenges [ 138 ].…”

Section: Poster Presentationsmentioning

confidence: 99%

30th Annual GP2A Medicinal Chemistry Conference

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Only a few E3 ubiquitin ligases were targeted, suggesting that a large pool of E3 ligases is potentially available for targeted protein degradation. The discovery of novel E3 ligases with novel binding ligand could lead to the design of new PROTACs for diseases that are still incurable today [31,32].…”

Section: Fig 3 Schematic Representation Of the Structure And Function...mentioning

confidence: 99%

Ubiquitin and its role in proteolisis: the 2004 Nobel prize in chemistry

Matyshevska¹,

Grigorieva²,

Danilova³

et al. 2022

Ukr.Biochem.J.

View full text Add to dashboard Cite

In the early 1980-s, Aaron Ciechanover, Avram Hershko, and Irwin Rose discovered one of the most important cyclic cellular processes – a regulated ATP-dependent protein degradation, for which they were awarded the 2004 Nobel Prize in Chemistry. These scientists proved the existence of a non-lysosomal proteolysis pathway and completely changed the perception of intracellular protein degradation mechanisms. They demonstrated pre-labelling of a doomed protein in a cell with a biochemical marker called ubiquitin. Polyubiquitylation of a protein as a signal for its proteolysis was a new mechanism discovered as a result of collaborative efforts of three scientists on isolation of enzymes involved in this sequential process, clarification of the biochemical stages, and substantiating the energy dependence mechanism. The article contains biographical data of the Nobel laureates, the methods applied, and the history of the research resulted in the discovery of the phenomenon of proteasomal degradation of ubiquitin-mediated proteins. Keywords: PROTAC, regulated protein degradation, ubiquitin, І. Rose, А. Ciechanover, А. Hershko

show abstract

PROTAC technology: A new drug design for chemical biology with many challenges in drug discovery

Cited by 43 publications

References 75 publications

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

30th Annual GP2A Medicinal Chemistry Conference

Ubiquitin and its role in proteolisis: the 2004 Nobel prize in chemistry

Contact Info

Product

Resources

About