Induction de proximité et dégradation de cibles thérapeutiques par les nouveaux dégradeurs : quels concepts, quels développements, quel futur ? DOI
Michèle Reboud‐Ravaux

Biologie Aujourd hui, Год журнала: 2024, Номер 218(1-2), С. 41 - 54

Опубликована: Янв. 1, 2024

The review is focused on recent drug discovery advances based targeted protein degradation strategies. This new area of research has exploded leading to the development potential drugs useful in a large variety human diseases. They first target disease relevant proteins difficult counteract with other classical strategies and extend now aggregates, organelles, nucleic acids or lipidic droplets. These degraders engaged either ubiquitin-proteasome system for PROTACs molecular glues (first generation), lysosomal via endosome-lysosome (LYTACs) autophagy-lysosome (ATTEC, AUTAC, AUTOTAC) (following generations degraders). have expanded from orthodox heterobifunctional ones derivatives such as homo-PROTACs, pro-PROTACs, CLIPTACs, HaloPROTACs, PHOTOTACs, Bac-PROTACs, AbTACs, ARN-PROTACs. small molecular-weight induce formation ternary complexes which implicate an ubiquitin ligase E3 allowing ubiquinitation followed by its proteasomal degradation. Lysosomal (LYTAC, ATTEC, specifically recognize extracellular membrane dysfunctional organelles transport them into lysosomes where they are degraded. overcome limitations observed degradations induced PROTAC demonstrate their treat diseases, especially neurodegenerative ones. Pharmaceutical companies at world level develop these targeting cancers, immuno-inflammatory diseases well Efficiency risks novel therapeutic discussed.

Язык: Английский

Applications of protein ubiquitylation and deubiquitylation in drug discovery DOI Creative Commons
Yilin Chen, Haoan Xue, Jianping Jin

и другие.

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(5), С. 107264 - 107264

Опубликована: Апрель 5, 2024

The ubiquitin-proteasome system (UPS) is the major machinery mediating specific protein turnover in eukaryotic cells. By ubiquitylating unwanted, damaged, or harmful proteins and driving their degradation, UPS involved many important cellular processes. Several new UPS-based technologies, including molecular glue degraders PROTACs (Proteolysis-targeting chimeras) to promote DUBTACs (deubiquitinase-targeting increase stability, have been developed. specifically inducing interactions between different ubiquitin ligases targeted that are not otherwise related, degrade via system; contrast, by proximity of deubiquitinases, created clear degradable polyubiquitin chains stabilize proteins. In this review, we summarize recent research progress degraders, PROTACs, applications. We discuss immunomodulatory drugs (IMiDs), sulfonamides, CDK-targeting development PROTACs. also introduce principle DUBTAC its Finally, propose a few future directions these three technologies related homeostasis.

Язык: Английский

Процитировано

21
Molecular glue degraders: exciting opportunities for novel drug discovery DOI
Thomas Lemaître, Marie Cornu, Florian Schwalen

и другие.

Expert Opinion on Drug Discovery, Год журнала: 2024, Номер 19(4), С. 433 - 449

Опубликована: Янв. 19, 2024

Introduction Molecular Glue Degraders (MGDs) is a concept that refers to class of compounds facilitate the interaction between two proteins or molecules within cell. These act as bridge enhances specific Protein-Protein Interactions (PPIs). Over past decade, this technology has gained attention potential strategy target were traditionally considered undruggable using small molecules.

Язык: Английский

Процитировано

10
Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation DOI Creative Commons
Chrysanthi Kagiou, José A. Cisneros, Jakob Farnung

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июнь 26, 2024

Abstract Targeted protein degradation (TPD) relies on small molecules to recruit proteins E3 ligases induce their ubiquitylation and by the proteasome. Only a few of approximately 600 human are currently amenable this strategy. This limits actionable target space clinical opportunities thus establishes necessity expand additional ligases. Here we identify characterize SP3N, specific degrader prolyl isomerase FKBP12. SP3N features minimal design, where known FKBP12 ligand is appended with flexible alkylamine tail that conveys properties. We found precursor metabolized an active aldehyde species recruits SCF FBXO22 ligase for degradation. Target engagement occurs via covalent adduction Cys326 in C-terminal domain, which critical ternary complex formation, mechanism conserved two recently reported alkylamine-based degraders NSD2 XIAP, establishing tethering hijacking as generalizable TPD

Язык: Английский

Процитировано

10
Ubiquitin E3 ligases assisted technologies in protein degradation: Sharing pathways in neurodegenerative disorders and cancer DOI
Aastha Kaushik,

Somya Parashar,

Rashmi K. Ambasta

и другие.

Ageing Research Reviews, Год журнала: 2024, Номер 96, С. 102279 - 102279

Опубликована: Март 22, 2024

Язык: Английский

Процитировано

8
Emerging strategies for prospective discovery of molecular glue degraders DOI
Baiyun Wang, Shiyun Cao, Ning Zheng

и другие.

Current Opinion in Structural Biology, Год журнала: 2024, Номер 86, С. 102811 - 102811

Опубликована: Апрель 9, 2024

Язык: Английский

Процитировано

8
Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders DOI Creative Commons
Corentin Bouvier, Rachel Lawrence,

Francesca Cavallo

и другие.

Cells, Год журнала: 2024, Номер 13(7), С. 578 - 578

Опубликована: Март 26, 2024

Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding ubiquitin ligase. More generally referred as bifunctional degraders, PROTACs have led the way in field targeted protein (TPD), with several currently undergoing clinical testing. Alongside single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered viable approach for development therapeutics, driven advances rational discovery approaches. This review focuses on drug respect within proteasome system, including analysis mechanistic concepts approaches, an overview current pre-clinical degrader status oncology, neurodegenerative inflammatory disease.

Язык: Английский

Процитировано

7
Targeted protein degradation in CNS disorders: a promising route to novel therapeutics? DOI Creative Commons

Sandra Kuemper,

Andrew G. Cairns, Kristian Birchall

и другие.

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Апрель 15, 2024

Targeted protein degradation (TPD) is a rapidly expanding field, with various PROTACs (proteolysis-targeting chimeras) in clinical trials and molecular glues such as immunomodulatory imide drugs (IMiDs) already well established the treatment of certain blood cancers. Many current approaches are focused on oncology targets, leaving numerous potential applications underexplored. Targeting proteins for offers novel therapeutic route targets whose inhibition remains challenging, aggregates neurodegenerative diseases. This mini review focuses prospect utilizing TPD disease particularly PROTAC glue formats opportunities CNS E3 ligases. Some key challenges modalities including design degrader molecules, drug delivery brain barrier penetrance will be discussed.

Язык: Английский

Процитировано

6
Morphological profiling for drug discovery in the era of deep learning DOI Creative Commons
Qiaosi Tang, Ranjala Ratnayake, Gustavo Seabra

и другие.

Briefings in Bioinformatics, Год журнала: 2024, Номер 25(4)

Опубликована: Май 23, 2024

Abstract Morphological profiling is a valuable tool in phenotypic drug discovery. The advent of high-throughput automated imaging has enabled the capturing wide range morphological features cells or organisms response to perturbations at single-cell resolution. Concurrently, significant advances machine learning and deep learning, especially computer vision, have led substantial improvements analyzing large-scale high-content images high throughput. These efforts facilitated understanding compound mechanism action, repurposing, characterization cell morphodynamics under perturbation, ultimately contributing development novel therapeutics. In this review, we provide comprehensive overview recent field profiling. We summarize image analysis workflow, survey broad spectrum strategies encompassing feature engineering– learning–based approaches, introduce publicly available benchmark datasets. place particular emphasis on application pipeline, covering segmentation, representation multimodal learning. Additionally, illuminate discovery highlight potential challenges opportunities field.

Язык: Английский

Процитировано

5
SuFEx-based chemical diversification for the systematic discovery of CRBN molecular glues DOI Creative Commons
Trever R. Carter, Natalia Milosevich, Lucas Dada

и другие.

Bioorganic & Medicinal Chemistry, Год журнала: 2024, Номер 104, С. 117699 - 117699

Опубликована: Апрель 1, 2024

Molecular glues are small molecules that stabilize protein–protein interactions, enabling new molecular pharmacologies, such as targeted protein degradation. They offer advantages over proteolysis targeting chimeras (PROTACs), which present challenges associated with the size and properties of heterobifunctional constructions, but lack rational design principles analogous to PROTACs. One notable exception is ability alter structure Cereblon (CRBN)-based redirect their activity toward neo-substrate proteins. We took a focused approach modifying CRBN ligand, 5′-amino lenalidomide, its specificity using high-throughput chemical diversification by parallelized sulfur(VI)-fluoride exchange (SuFEx) transformations. synthesized 3,000 analogs lenalidomide this screened crude products phenotypic screen for cell viability, identifying dozens differentiated activity. characterized four compounds degrade G-to-S phase transition 1 (GSPT1) protein, providing proof-of-concept model SuFEx-based discovery glues.

Язык: Английский

Процитировано

3
Extrapolating Lessons from Targeted Protein Degradation to Other Proximity-Inducing Drugs DOI Creative Commons
Georg E. Winter

ACS Chemical Biology, Год журнала: 2024, Номер unknown

Опубликована: Сен. 12, 2024

Targeted protein degradation (TPD) is an emerging pharmacologic strategy. It relies on small-molecule "degraders" that induce proximity of a component E3 ubiquitin ligase complex and target to ubiquitination subsequent proteasomal degradation. Essentially, degraders thus expand the function ligases, allowing them degrade proteins they would not recognize in absence small molecule. Over past decade, insights gained from identifying, designing, characterizing various have significantly enhanced our understanding TPD mechanisms, precipitating rational degrader discovery strategies. In this Account, I aim explore how these can be extrapolated anticipate both opportunities challenges utilizing overarching concept proximity-inducing pharmacology manipulate other cellular circuits for dissection biological mechanisms therapeutic purposes.

Язык: Английский

Процитировано

3