PROTAC<sup>®</sup> technology and potential for its application in infection control DOI Creative Commons
M. A. Zakharova, М. В. Чудинов

Fine Chemical Technologies, Journal Year: 2024, Volume and Issue: 19(3), P. 214 - 231

Published: July 6, 2024

Objectives. To describe the pharmaceutical technology of controlled degradation protein molecules (PROTAC ® , Proteolysis Targeting Chimera), approaches to design PROTAC molecule, methods ligand and linker selection synthesis, as well application this in dealing with a variety diseases possible limitations its use. Results. The review covers 77 sources, mostly from 2020–2023. outlines principle technology: construction chimeric molecule consisting three fragments. One fragment specifically binds biotarget, another recruits proteolytic system host cell, third them together. main areas current development are described herein, opportunities fight against different types infectious diseases. Conclusion. potential use combat cancer neurodegenerative, autoimmune, is shown.

Language: Английский

Proximity-Based Modalities for Biology and Medicine DOI Creative Commons
Xingui Liu, Alessio Ciulli

ACS Central Science, Journal Year: 2023, Volume and Issue: 9(7), P. 1269 - 1284

Published: July 14, 2023

Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of processes high selectivity has the potential to substantially expand target space. A plethora proximity-based modalities proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines mechanisms molecules based on induced proximity, including protein degraders, blockers, stabilizers, inducers post-translational modifications, agents cell therapy, discusses challenges that field must address mature unlock translation in biology medicine.

Language: Английский

Citations

85
Auto-RapTAC: A Versatile and Sustainable Platform for the Automated Rapid Synthesis and Evaluation of PROTAC DOI

Jiexuan Chen,

Mingfei Wu,

Jun Mo

et al.

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

Published: Jan. 4, 2025

The tedious synthesis and limited throughput biological evaluation remain a great challenge for discovering new proteolysis targeting chimera (PROTAC). To rapidly identify potential PROTAC lead compounds, we report platform named Auto-RapTAC. Based on the modular characteristic of molecule, streamlined workflow that integrates lab automation with "click chemistry" joint building-block libraries was constructed. This facilitates autonomous generation variety PROTACs, each distinct linkers E3 ligase ligands, all stored in biocompatible solutions. ready-for-screening (R4S) approach, when paired fluorescence-based assays, enables efficient assessment degradation activity high-throughput manner. further test capability platform, six PROTACs target CDK2, CDK12, BCL6 within mere 8-day time frame target. In all, this could find broad application not only but also rapid development novel heterobifunctional modalities.

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
Development of versatile solid-phase methods for syntheses of PROTACs with diverse E3 ligands DOI
Hanqiao Xu, Takashi Kurohara, Nobumichi Ohoka

et al.

Bioorganic & Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 86, P. 117293 - 117293

Published: April 26, 2023

Language: Английский

Citations

7
PROTAC‐Mediated HDAC7 Protein Degradation Unveils Its Deacetylase‐Independent Proinflammatory Function in Macrophages DOI Creative Commons

Kailibinuer Kadier,

Tian Niu,

Baoli Ding

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: July 25, 2024

Abstract Class IIa histone deacetylases (Class HDACs) play critical roles in regulating essential cellular metabolism and inflammatory pathways. However, dissecting the specific of each class HDAC isoform is hindered by pan‐inhibitory effect current inhibitors a lack tools to probe their functions beyond epigenetic regulation. In this study, novel PROTAC‐based compound B4 developed, which selectively targets degrades HDAC7, resulting effective attenuation set proinflammatory cytokines both lipopolysaccharide (LPS)‐stimulated macrophages mouse model. By employing as molecular probe, evidence found for previously explored role HDAC7 that surpasses its deacetylase function, suggesting broader implications processes. Mechanistic investigations reveal involvement Toll‐like receptor 4 (TLR4) signaling pathway directly interacting with TNF receptor‐associated factor 6 TGFβ‐activated kinase 1 (TRAF6‐TAK1) complex, thereby initiating activation downstream mitogen‐activated protein kinase/nuclear factor‐κB (MAPK/NF‐κB) cascade subsequent gene transcription. This study expands insight into HDAC7's within intricate networks highlights therapeutic potential target anti‐inflammatory treatments.

Language: Английский

Citations

2
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
PROTAC<sup>®</sup> technology and potential for its application in infection control DOI Creative Commons
M. A. Zakharova, М. В. Чудинов

Fine Chemical Technologies, Journal Year: 2024, Volume and Issue: 19(3), P. 214 - 231

Published: July 6, 2024

Objectives. To describe the pharmaceutical technology of controlled degradation protein molecules (PROTAC ® , Proteolysis Targeting Chimera), approaches to design PROTAC molecule, methods ligand and linker selection synthesis, as well application this in dealing with a variety diseases possible limitations its use. Results. The review covers 77 sources, mostly from 2020–2023. outlines principle technology: construction chimeric molecule consisting three fragments. One fragment specifically binds biotarget, another recruits proteolytic system host cell, third them together. main areas current development are described herein, opportunities fight against different types infectious diseases. Conclusion. potential use combat cancer neurodegenerative, autoimmune, is shown.

Language: Английский

Citations

0