A plug-and-play monofunctional platform for targeted degradation of extracellular proteins and vesicles DOI Creative Commons
Shasha Yao, Yi Wang, Qian Tang

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 22, 2024

Existing strategies use bifunctional chimaeras to mediate extracellular protein degradation. However, these rely on specific lysosome-trafficking receptors facilitate lysosomal delivery, which may raise resistance concerns due intrinsic cell-to-cell variation in receptor expression and mutations or downregulation of the receptors. Another challenge is establishing a universal platform applicable multiple scenarios. Here, we develop MONOTAB (MOdified NanOparticle with TArgeting Binders), plug-and-play monofunctional degradation that can drag targets into lysosomes for harnesses inherent lysosome-targeting ability certain nanoparticles obviate dependency hook effect. To achieve high modularity programmable target specificity, utilize streptavidin-biotin interaction immobilize antibodies other targeting molecules nanoparticles, through an antibody mounting approach by direct binding. Our study reveals induce efficient diverse therapeutic targets, including membrane proteins, secreted even vesicles. methods but receptors, raising issues. authors MONOTAB, degrades proteins vesicles without dependency.

Language: Английский

Identification and Development of BRD9 Chemical Probes DOI Creative Commons
Ester Colarusso, Maria Giovanna Chini, Giuseppe Bifulco

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(3), P. 392 - 392

Published: March 19, 2024

The development of BRD9 inhibitors involves the design and synthesis molecules that can specifically bind protein, interfering with function chromatin-remodeling complex ncBAF, main advantage modulating gene expression controlling cellular processes. Here, we summarize work conducted over past 10 years to find new binders, an emphasis on their structure–activity relationships, efficacies, selectivities in preliminary studies. is expressed a variety cancer forms, hence, its inhibition holds particular significance research. However, it crucial note expanding research field, particularly degraders, may uncover therapeutic potentials.

Language: Английский

Citations

4
Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins DOI Creative Commons
Melisa Halilovic, Mohamed Abdelsalam,

Joanna Zabkiewicz

et al.

Leukemia, Journal Year: 2024, Volume and Issue: 38(12), P. 2561 - 2572

Published: Sept. 17, 2024

Language: Английский

Citations

4
Advances in designing ternary complexes: Integrating in-silico and biochemical methods for PROTAC optimisation in target protein degradation DOI Creative Commons
Shareef Shaik,

Prasanna Kumar Reddy Gayam,

Manish Chaudhary

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 153, P. 107868 - 107868

Published: Oct. 4, 2024

Language: Английский

Citations

4
A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins DOI Creative Commons
Suzanne Ackloo, Fengling Li,

Magda Szewczyk

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 4, 2024

Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present systematic approach to scale up the and characterization small molecule ligands for WD40 repeat (WDR) family. We developed comprehensive suite protocols production, crystallography, biophysical, biochemical, cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection followed by machine learning (DEL-ML) predict from virtual libraries yielded first-in-class, drug-like 7 16 WDR domains screened, thus demonstrating broader ligandability WDRs. This study establishes template evaluation family wide provides an extensive resource biochemical tools, knowledge, discover potential therapeutics this highly disease-relevant, but underexplored target class.

Language: Английский

Citations

4
DNA Tetrahedron-Driven Multivalent Proteolysis-Targeting Chimeras: Enhancing Protein Degradation Efficiency and Tumor Targeting DOI
Shiqing Li, Tao Zeng, Zhixing Wu

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Proteolysis-targeting chimeras (PROTACs) are dual-functional molecules composed of a protein interest (POI) ligand and an E3 ligase connected by linker, which can recruit POI ligases simultaneously, thereby inducing the degradation showing great potential in disease treatment. A challenge developing PROTACs is design linkers modification ligands to establish multifunctional platform that enhances efficiency antitumor activity. As programmable modifiable nanomaterial, DNA tetrahedron precisely assemble selectively recognize flexibly adjust distance between molecules, making them ideal linkers. Herein, we developed multivalent PROTAC based on tetrahedron, named AS-TD2-PRO. Using as combined modules targeting tumor cells, recognizing ligases, multiple together. We took undruggable target signal transducer activator transcription 3 (STAT3), associated with etiology progression variety malignant tumors, example this study. AS-TD2-PRO two STAT3 recognition demonstrated good enhancing tumor-specific compared traditional bivalent PROTACs. Furthermore, mouse model, superior therapeutic activity was observed. Overall, tetrahedron-driven both serve proof principle for introduce promising avenue cancer treatment strategies.

Language: Английский

Citations

0
Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept DOI
Scott J. Hughes,

Wojciech J. Stec,

Colin Davies

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract Prospective discovery of molecular glues degraders for a specific therapeutic target protein interest is an emerging strategy in drug discovery. Modification pre-existing ligands with fragments that can alter the surface lead to creation novel compounds (‘’targeted glues’’) able induce neo-interactions between and E3 ligase, resulting targeted degradation. By screening library potential BRD9 glue compounds, we have discovered potent selective, reversibly covalent degrader, AMPTX-1 . Co-immunoprecipitation-mass spectrometry experiments demonstrated cell treatment induces selective recruitment ligase DCAF16. Degradation dependent on engagement Cys58 DCAF16 formation adduct facilitated by ternary complex BRD9. degradation achieved viv o after oral dosing, demonstrating viable be drug-like, orally bioavailable promising vivo activity.

Language: Английский

Citations

0
Implications of frequent hitter E3 ligases in targeted protein degradation screens DOI
Xiaoyu Zhang, Gabriel M. Simon, Benjamin F. Cravatt

et al.

Nature Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Language: Английский

Citations

0
Discovery of DCAF16 Binders for Targeted Protein Degradation DOI
Miguel Campos,

Isabella A. Riha,

Chenlu Zhang

et al.

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Conventional small-molecule drugs primarily operate by inhibiting protein function, but this approach is limited when proteins lack well-defined ligand-binding pockets. Targeted degradation (TPD) offers an alternative harnessing cellular pathways to eliminate specific proteins. Recent studies have expanded the potential of TPD identifying additional E3 ligases, with DCAF16 emerging as a promising candidate for facilitating through both proteolysis-targeting chimera (PROTAC) and molecular glue mechanisms. In study, we revisited previously reported compound discovered that it covalently binds DCAF16. We further optimized into FKBP12-targeting PROTAC, MC-25B. This PROTAC engages at cysteines C177-179, leading nuclear-localized FKBP12. demonstrated versatility recruiter degrading endogenous Compared first-generation DCAF16-based which was derived from fragment electrophile, recruiter-based exhibits improved proteome-wide selectivity.

Language: Английский

Citations

0
Workflow for E3 Ligase Ligand Validation for PROTAC Development DOI Creative Commons

Nebojša Miletić,

Janik Weckesser, Thorsten Mosler

et al.

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 11, 2025

Proteolysis targeting chimeras (PROTACs) have gained considerable attention as a new modality in drug discovery. The development of PROTACs has been mainly focused on using CRBN (Cereblon) and VHL (Von Hippel-Lindau ligase) E3 ligase ligands. However, the size human family, newly developed ligands, favorable druggability some families hold promise that novel degraders with unique pharmacological properties will be designed future this large space. Here, we workflow aiming to improve streamline evaluation ligand efficiency for PROTAC assessment corresponding "degradable" target space broad-spectrum kinase inhibitors well-established VH032 validation system. Our study revealed linker attachment points are highly efficient degradation well pitfalls when protein readout. For instance, cytotoxicity was identified major mechanism leading PROTAC- VHL-independent degradation. combination negative controls, competition by parent compounds, neddylation proteasome essential distinguish between VHL-dependent -independent events. We share here findings limitations our hope provide guidance evaluations systems degrader development.

Language: Английский

Citations

0
Application of DELs for E3 Ligase Ligand Discovery and Targeted Protein Degradation DOI
Marie L. Malone,

Nicholas A. Sanchez,

Shimin Hu

et al.

Royal Society of Chemistry eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 134 - 156

Published: Feb. 21, 2025

Targeted protein degradation (TPD) provides new therapeutic opportunities beyond traditional inhibitors. TPD relies on the ability to induce proximity between an E3 ligase and target of interest, harnessing ubiquitin proteasome system ubiquitylate degrade target. This can be induced by either monofunctional ligands (molecular glues) or bifunctional molecules that tether ligases together. DNA encoded libraries (DELs) provide rapid access diverse chemical space for ligand discovery and, their design, facilitate development both molecular glues degraders.

Language: Английский

Citations

0