ProteoCure: A European network to fine-tune the proteome DOI Creative Commons
Olivier Coux, Rosa Farrás, Mohamad Abbas

et al.

Biochimie, Journal Year: 2024, Volume and Issue: 226, P. 4 - 9

Published: June 18, 2024

Proteins are essential molecular actors in every cellular process. From their synthesis to degradation, they subject continuous quality control mechanisms ensure that fulfil needs proper and timely fashion. Proteostasis is a key process allowing cells or organisms maintain an appropriate but dynamic equilibrium of proteome (the ensemble all proteins). It relies on multiple together the level, fate function individual proteins, elimination abnormal ones. The proteostasis network for development adaptation environmental changes challenges. Its dysfunctions can lead accumulation deleterious proteins or, conversely, excessive degradation beneficial ones, implicated many diseases such as cancers, neurodegeneration, developmental aging disorders. Manipulating this abundance selected target therefore strategy with enormous therapeutic biotechnological potential. ProteoCure COST Action gathers more than 350 researchers teams (31 countries represented) from academic, clinical, industrial sectors, who share conviction our understanding mature enough develop novel highly specific therapies based selective tunning protein levels. Towards objective, organizes community-building activities foster synergies among its participants reinforce training next generation European researchers. ambition knowledge-based creative exchange hub normal pathologic proteostasis, focusing developing innovative tools modulating level protein(s).

Language: Английский

Journey of PROTAC: From Bench to Clinical Trial and Beyond DOI

Kyli Berkley,

Julian Zalejski, Nidhi Sharma

et al.

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Proteolysis-targeting chimeras (PROTACs) represent a transformative advancement in drug discovery, offering method to degrade specific intracellular proteins. Unlike traditional inhibitors, PROTACs are bifunctional molecules that target proteins for elimination, enabling the potential treatment of previously "undruggable" This concept, pioneered by Crews and his team, introduced use small link protein an E3 ubiquitin ligase, inducing ubiquitination subsequent degradation protein. By promoting rather than merely inhibiting function, present novel therapeutic strategy with enhanced specificity effectiveness, especially areas such as cancer neurodegenerative diseases. Since their initial field PROTAC research has rapidly expanded numerous now designed wide range disease-relevant The substantial research, investment, collaboration across academia pharmaceutical industry reflect growing interest PROTACs. Review discusses journey from discovery clinical trials, highlighting advancements challenges. Additionally, recent developments fluorescent photogenic PROTACs, used real-time tracking degradation, presented, showcasing evolving targeted therapy.

Language: Английский

Citations

3
Finding a needle in the haystack: ADME and pharmacokinetics/pharmacodynamics characterization and optimization toward orally available bifunctional protein degraders DOI
Giulia Apprato, Giulia Caron, Gauri Deshmukh

et al.

Expert Opinion on Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 16, 2025

Degraders are an increasingly important sub-modality of small molecules as illustrated by ever-expanding number publications and clinical candidate in human trials. Nevertheless, their preclinical optimization ADME PK/PD properties has remained challenging. Significant research efforts being directed to elucidate underlying principles derive rational strategies. In this review the authors summarize current best practices terms vitro assays vivo experiments. Furthermore, collate comment on understanding optimal physicochemical characteristics impact absorption, distribution, metabolism excretion including knowledge Drug-Drug interactions. Finally, describe Pharmacokinetic prediction Pharmacokinetic/Pharmacodynamic -concepts unique degraders how implement these projects. Despite many recent advances field, continued will further our design regarding degrader optimization. Machine-learning computational approaches become once larger, more robust datasets available. tissue-targeting (particularly Central Nervous System be studied efficacious drug regimens that capitalize catalytic mode action. additional specialized (e.g. covalent degraders, LOVdegs) can enrich field offer interesting alternative approaches.

Language: Английский

Citations

1
Design and Discovery of Preclinical Candidate LYG-409 as a Highly Potent and Selective GSPT1 Molecular Glue Degraders DOI
Yanqing Zhang, Wenjing Liu, Chao Tong

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Molecular glue degraders induce "undruggable" protein degradation by a proximity-induced effect. Inspired the clinical success of immunomodulatory drugs, we aimed to design novel molecular targeting GSPT1. Here, report series GSPT1 degraders. LYG-409, 2H-chromene derivative, was identified as potent, selective, and orally bioavailable degrader with excellent antitumor activity in vivo (anti-Acute Myeloid Leukemia MV4–11 xenograft model: TGI = 94.34% at 30 mg/kg; prostate cancer 22Rv1 104.49% 60 mg/kg) vitro (KG-1 cells: IC50 9.50 ± 0.71 nM, DC50 7.87 nM) mediated In conclusion, LYG-409 exhibits potent activity, demonstrating promising therapeutic efficacy favorable safety profile. However, its potential drug resistance profile needs be thoroughly evaluated comparison existing treatments. We hope can provide valuable direction for development

Language: Английский

Citations

0
Role of TRIM24 in the regulation of proteasome-autophagy crosstalk in bortezomib-resistant mantle cell lymphoma DOI Creative Commons
Corentin Bouvier, María Gonzalez-Santamarta, Núria Profitós-Pelejà

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 17, 2025

Resistance to bortezomib (BTZ) represents a major bottleneck continue using this proteasome inhibitor in the treatment of mantle cell lymphoma (MCL). In study, we investigated mechanisms by which TRIM24 (tripartite motif-containing 24), ubiquitin ligase enriched ubiquitome BTZ-resistant MCL cells, modulates proteasome-autophagy crosstalk. The localization and stability were differentially influenced inhibition or autophagy cells with acquired BTZ resistance (ZBR). Moreover, genetic deletion gene ZBR (ZBRTRIM24 KO) effectively impaired proliferation without impacting degradation proteaphagy that is typically observed cells. Notably, pre-treatment proteolysis-targeting chimera (PROTAC) targeting (dTRIM24) successfully restored susceptibility, underscoring critical role mediating inhibition. Interestingly, combined apoptogenic activity dTRIM24 was preserved second clone (JBR) lacks functional p53, indicating tumor suppressor not required for effect. Furthermore, demonstrated reducing protein levels via activity, facilitating efficient apoptosis induction exposed dTRIM24/BTZ combination. Mechanistically, promoted formation K48-linked chains their association subunits, specifically Taken together, these findings reveal plays pivotal regulatory crosstalk between modulating chain abundance, thereby influencing activation one other proteolytic pathway.

Language: Английский

Citations

0
Design, synthesis, and biological evaluation of RIPK1-targeting PROTACs DOI
Hefeng Zhang,

S.S Zhang,

Tieyu Wang

et al.

Molecular Diversity, Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

Language: Английский

Citations

0
To homeostasis and beyond! Recent advances in the medicinal chemistry of heterobifunctional derivatives DOI

Diana Castagna,

Benoit Gourdet,

Roland Hjerpe

et al.

Progress in medicinal chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 61 - 160

Published: Jan. 1, 2024

Language: Английский

Citations

1
ProteoCure: A European network to fine-tune the proteome DOI Creative Commons
Olivier Coux, Rosa Farrás, Mohamad Abbas

et al.

Biochimie, Journal Year: 2024, Volume and Issue: 226, P. 4 - 9

Published: June 18, 2024

Proteins are essential molecular actors in every cellular process. From their synthesis to degradation, they subject continuous quality control mechanisms ensure that fulfil needs proper and timely fashion. Proteostasis is a key process allowing cells or organisms maintain an appropriate but dynamic equilibrium of proteome (the ensemble all proteins). It relies on multiple together the level, fate function individual proteins, elimination abnormal ones. The proteostasis network for development adaptation environmental changes challenges. Its dysfunctions can lead accumulation deleterious proteins or, conversely, excessive degradation beneficial ones, implicated many diseases such as cancers, neurodegeneration, developmental aging disorders. Manipulating this abundance selected target therefore strategy with enormous therapeutic biotechnological potential. ProteoCure COST Action gathers more than 350 researchers teams (31 countries represented) from academic, clinical, industrial sectors, who share conviction our understanding mature enough develop novel highly specific therapies based selective tunning protein levels. Towards objective, organizes community-building activities foster synergies among its participants reinforce training next generation European researchers. ambition knowledge-based creative exchange hub normal pathologic proteostasis, focusing developing innovative tools modulating level protein(s).

Language: Английский

Citations

0