Nondegradative Synthetic Molecular Glues Enter the Clinic DOI Creative Commons

Maximilian Repity,

Robin C. E. Deutscher,

Felix Hausch

et al.

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

Published: April 14, 2025

Molecular glues are small molecules that can induce or stabilize protein–protein interactions between proteins inside cells. Unlike classical molecule drugs, molecular target challenging disease‐causing lacking well‐defined binding pockets. Nature has repeatedly used this mode of action, but identifying for new been a major challenge. Recently, manmade glues, inspired by natural products, KRas, entered clinical trials although KRas is cancer long thought to be undruggable. Here, how these initially discovered and optimized provide several advanced drug candidates various KRas‐dependent types outlined. The insights obtained class modalities further summarized. These results showcase do not rely on protein degradation benefits targets.

Language: Английский

Targeted protein degradation directly engaging lysosomes or proteasomes DOI Creative Commons
Jiseong Kim, Insuk Byun, Do Young Kim

et al.

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(7), P. 3253 - 3272

Published: Jan. 1, 2024

This review delineates emerging technologies for targeted protein degradation that directly involve lysosomes or proteasomes. It explores their unique features, advantages, and limitations, offering perspectives on future therapeutic applications.

Language: Английский

Citations

28
Targeted protein degradation: advances in drug discovery and clinical practice DOI Creative Commons
Guangcai Zhong, Xiaoyu Chang, Weilin Xie

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 6, 2024

Abstract Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing stark contrast to traditional approaches like small molecule inhibitors that primarily focus on inhibiting function. This advanced technology capitalizes the cell’s intrinsic proteolytic systems, including proteasome and lysosomal pathways, selectively eliminate disease-causing proteins. TPD not only enhances efficacy of treatments but also expands scope applications. Despite its considerable potential, faces challenges related properties drugs their rational design. review thoroughly explores mechanisms clinical advancements TPD, from initial conceptualization practical implementation, with particular proteolysis-targeting chimeras molecular glues. In addition, delves into emerging technologies methodologies aimed at addressing these enhancing efficacy. We discuss significant trials highlight promising outcomes associated drugs, illustrating potential transform treatment landscape. Furthermore, considers benefits combining other therapies enhance overall effectiveness overcome drug resistance. The future directions applications are explored, presenting an optimistic perspective further innovations. By offering comprehensive overview current innovations faced, this assesses transformative revolutionizing development setting stage for new era medical therapy.

Language: Английский

Citations

24
Targeting the undruggables—the power of protein degraders DOI Creative Commons
Chao Zhang, Yongbo Liu, Guangchen Li

et al.

Science Bulletin, Journal Year: 2024, Volume and Issue: 69(11), P. 1776 - 1797

Published: March 29, 2024

Undruggable targets typically refer to a class of therapeutic that are difficult target through conventional methods or have not yet been targeted, but great clinical significance. According statistics, over 80% disease-related pathogenic proteins cannot be targeted by current treatment methods. In recent years, with the advancement basic research and new technologies, development various technologies mechanisms has brought perspectives overcome challenging drug targets. Among them, protein degradation technology is breakthrough strategy for This can specifically identify directly degrade utilizing inherent pathways within cells. form includes types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting (AUTAC), (AUTOTAC), degrader-antibody conjugate (DAC). article systematically summarizes application in degraders Finally, looks forward future direction prospects technology.

Language: Английский

Citations

20
In silico modeling of targeted protein degradation DOI Creative Commons
Wenxing Lv,

Xiaojuan Jia,

Bowen Tang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 289, P. 117432 - 117432

Published: Feb. 20, 2025

Language: Английский

Citations

2
New insights into protein–protein interaction modulators in drug discovery and therapeutic advance DOI Creative Commons
Hossam Nada, Yongseok Choi, Sung-Do Kim

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Dec. 5, 2024

Abstract Protein-protein interactions (PPIs) are fundamental to cellular signaling and transduction which marks them as attractive therapeutic drug development targets. What were once considered be undruggable targets have become increasingly feasible due the progress that has been made over last two decades rapid technological advances. This work explores influence of innovations on PPI research development. Additionally, diverse strategies for discovering, modulating, characterizing PPIs their corresponding modulators examined with aim presenting a streamlined pipeline advancing PPI-targeted therapeutics. By showcasing carefully selected case studies in modulator discovery development, we illustrate efficacy various identifying, optimizing, overcoming challenges associated design. The valuable lessons insights gained from identification, optimization, approval discussed demonstrating transitioned beyond early-stage now represent prime opportunity significant potential. examples encompass those developed cancer, inflammation immunomodulation, well antiviral applications. perspective aims establish foundation effective targeting modulation using pave way future

Language: Английский

Citations

14
JBI-802: the first orally available LSD1/HDAC6 dual inhibitor to enter clinical trials DOI
Jingya Zhang,

Xiangli Ren,

Yihui Song

et al.

Expert Opinion on Therapeutic Patents, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Introduction Lysine-specific demethylase 1 (LSD1) and histone deacetylase 6 (HDAC6) are key epigenetic regulators involved in demethylation deacetylation, processes that impact chromatin structure gene expression. JBI-802 marks a major advancement as the first novel, orally available LSD1/HDAC6 dual inhibitor currently clinical trials.

Language: Английский

Citations

1
The Structural Basis of the G Protein–Coupled Receptor and Ion Channel Axis DOI Creative Commons

Yulin Luo,

Liping Sun, Yao Peng

et al.

Current Research in Structural Biology, Journal Year: 2025, Volume and Issue: 9, P. 100165 - 100165

Published: Feb. 19, 2025

Sensory neurons play an essential role in recognizing and responding to detrimental, irritating, inflammatory stimuli from our surroundings, such as pain, itch, cough, neurogenic inflammation. The transduction of these physiological signals is chiefly mediated by G protein-coupled receptors (GPCRs) ion channels. binding ligands GPCRs triggers a signaling cascade, recruiting proteins or β-arrestins, which subsequently interact with channels (e.g., GIRK TRP channels). This interaction leads the sensitization activation channels, initiating neuron's protective mechanisms. review delves into complex interplay between that underpin processes, particular focus on structural biology enhancing comprehension. Through unraveling intricacies GPCR-ion channel axis, we aim shed light sophisticated intermolecular dynamics within pivotal membrane protein families, ultimately guiding development precise therapeutic interventions.

Language: Английский

Citations

1
Identification and characterization of ternary complexes consisting of FKBP12, MAPRE1 and macrocyclic molecular glues DOI Creative Commons
Michael Salcius, Antonin Tutter, Marianne Fouché

et al.

RSC Chemical Biology, Journal Year: 2025, Volume and Issue: 6(5), P. 788 - 799

Published: Jan. 1, 2025

Many disease-relevant and functionally well-validated targets are difficult to drug. Their poorly defined 3D structure without deep hydrophobic pockets makes the development of ligands with low molecular weight high affinity almost impossible. For these targets, incorporation into a ternary complex may be viable alternative modulate in most cases inhibit their function. Therefore, we interested methods identify characterize glues. In protein array screen 50 different macrocyclic FKBP12 against 2500 randomly selected proteins, glue compound was found recruit dimeric called MAPRE1 compound-dependent manner. The corresponding characterized by TR-FRET proximity assay native MS spectroscopy. Insights were obtained 2D NMR spectroscopy finally an X-ray structure, which revealed as 2 : exhibiting multiple interactions that occur exclusively lead significant cooperativity α. Using rationally guided synthesis series analogues led driven improvement stability complex. Furthermore, formation confirmed cellular NanoBiT assays, whose A max values correlate those from assay. experiments showed functional impact (inhibition) glues on interaction its intracellular partners.

Language: Английский

Citations

1
Proteomic approaches advancing targeted protein degradation DOI Creative Commons
Gajanan Sathe, Gopal P. Sapkota

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(11), P. 786 - 801

Published: Sept. 29, 2023

Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) molecular glue (MG) degraders (MGDs) represent the most advanced approaches, with some already used in clinical settings. Despite these advances, still faces many challenges, pertaining to both development of effective, selective, tissue-penetrant understanding their mode action. In this review, we focus on progress made addressing challenges. particular, discuss utility application recent proteomic as indispensable tools enable insights into degrader development, including target engagement, selectivity, efficacy, safety,

Language: Английский

Citations

22
Recent developments in molecular modeling tools and applications related to pharmaceutical and biomedical research DOI Creative Commons
Paola Peluso, Bezhan Chankvetadze

Journal of Pharmaceutical and Biomedical Analysis, Journal Year: 2023, Volume and Issue: 238, P. 115836 - 115836

Published: Nov. 3, 2023

In modern pharmaceutical and biomedical research, molecular modeling represents a useful tool to explore processes their mechanistic bases at the level. Integrating experimental virtual analysis is fruitful approach study ligand-receptor interaction in chemical, biochemical biological environments. these fields, docking dynamics are considered privileged techniques for (bio)macromolecules related complexes. This review aims present current landscape of research by examining selected representative applications published last years highlighting topics trends this field. Thus, systematic compilation all literature has not been attempted herein. After brief overview main theoretical computational tools used investigate mechanisms level, recent drug discovery, ligand binding studying protein conformation function will be discussed. Furthermore, specific sections devoted application unravelling enantioselective underlying enantioseparation chiral compounds interest as well new forms noncovalent interactivity identified The general aim provide reader with topic, advancements outlooks drawbacks pitfalls still affecting applicability methods field research.

Language: Английский

Citations

18