Dual-action kinase inhibitors influence p38α MAP kinase dephosphorylation DOI Creative Commons
Emily Jane Stadnicki, Hannes Ludewig, Ramasamy P. Kumar

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 122(1)

Published: Dec. 31, 2024

Reversible protein phosphorylation directs essential cellular processes including cell division, growth, death, inflammation, and differentiation. Because drives diverse diseases, kinases phosphatases have been targets for drug discovery, with some achieving remarkable clinical success. Most are activated by of their activation loops, which shifts the conformational equilibrium kinase toward active state. To turn off kinase, dephosphorylate these sites, but how conformation dynamic loop contributes to dephosphorylation was not known. answer this, we modulated human p38α ΜΑP existing inhibitors that bind stabilize specific inactive conformations. From identified three increase rate phospho-threonine PPM serine/threonine phosphatase WIP1. Hence, compounds “dual-action” simultaneously block site promote dephosphorylation. Our X-ray crystal structures phosphorylated bound dual-action reveal a shared flipped fully accessible phospho-threonine. In contrast, our structure apo reveals different an inaccessible phospho-threonine, thereby explaining increased upon inhibitor binding. These findings preference suggest unique approach improved potency specificity therapeutic inhibitors.

Language: Английский

Targeted Covalent Modification Strategies for Drugging the Undruggable Targets DOI
Tomonori Tamura,

Masaharu Kawano,

Itaru Hamachi

et al.

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

The term "undruggable" refers to proteins or other biological targets that have been historically challenging target with conventional drugs therapeutic strategies because of their structural, functional, dynamic properties. Drugging such undruggable is essential develop new therapies for diseases where current treatment options are limited nonexistent. Thus, investigating methods achieve drugging an important challenge in medicinal chemistry. Among the numerous methodologies drug discovery, covalent modification has emerged as a transformative strategy. attachment diverse functional molecules provides powerful platform creating highly potent and chemical tools well ability provide valuable information on structures dynamics targets. In this review, we summarize recent examples biomolecules development therapeutics overcome discovery challenges highlight how contribute toward particular, focus use chemistry drugs, identification, screening, artificial modulation post-translational modifications, cancer specific chemotherapies, nucleic acid-based therapeutics.

Language: Английский

Citations

1
Turnover atlas of proteome and phosphoproteome across mouse tissues and brain regions DOI
Wenxue Li, Abhijit Dasgupta, Ka Yang

et al.

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

Published: March 1, 2025

Language: Английский

Citations

1
Histamine N-methyltransferase (HNMT) as a potential auxiliary biomarker for predicting adaptability to anti-HER2 drug treatment in breast cancer patients DOI Creative Commons
Tzu‐Chun Cheng, Mien‐Chie Hung,

Lu-Hai Wang

et al.

Biomarker Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 9, 2025

Abstract Background Up to 23% of breast cancer patients recurred within a decade after trastuzumab treatment. Conversely, one trial found that with low HER2 expression and metastatic had positive response trastuzumab-deruxtecan (T-Dxd). This indicates relying solely on as single diagnostic marker predict the efficacy anti-HER2 drugs is insufficient. study highlights interaction between histamine N-methyltransferase (HNMT) an adjunct predictor for response. Furthermore, modulation by HNMT may explain why those still respond T-Dxd. Methods We investigated impact protein therapy in both vivo ex models patient-derived xenografts cell line-derived xenografts. Our analysis included Förster resonance energy transfer (FRET) assess strength proteins trastuzumab-resistant sensitive tumor tissues. Additionally, we used fluorescence lifetime imaging microscopy (FLIM), cleaved luciferase, immunoprecipitation dynamics HER2. evaluated influence activity binding antibodies their targets through flow cytometry. also observed nuclear translocation HNMT/HER2-ICD cells using fluorescent double staining DeltaVision microscopy. Finally, ChIP sequencing was employed identify target genes affected complex. Results potential auxiliary biomarker diagnosing + cancer. FRET demonstrated significant trastuzumab-sensitive tissue ( n = 50), suggesting treatment Mechanistic studies revealed contributes increased at transcriptional level, thereby impacting therapy. subset triple-negative cancers characterized overexpression be antibody–drug conjugates such Conclusions These findings offer crucial insights clinicians evaluating candidates therapy, especially HER2-low who could gain from T-Dxd Identifying help pinpoint would benefit

Language: Английский

Citations

0
TogoPhosTAC: A Ready-To-Go and Adaptable Targeted Protein Dephosphorylation System DOI Creative Commons
Po‐Han Chen,

Yu-Yu Chen,

Dong-Ting Ke

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

Abstract Phosphorylation targeting chimeras (PhosTACs) recruit phosphatases to dephosphorylate target proteins by proximity-induced protein interactions. However, recruiting a phosphatase subunit or holoenzyme using small molecules without compromising its activity adversely disturbing cellular function remains challenging. In addition, many do not have favorable activator binder currently. To overcome these limitations, here, we report an adapted mode of action, named togoPhosTAC, based on the molecule PhosTAC, engineered fusion FKBP12(F36V)-phosphatase, and lipid-based delivery system for targeted dephosphorylation. Through nanoparticles, delivered pre-fused complex PhosTACs FKBP12(F36V)-phosphatases in mRNA format directly rapid efficient intracellular The togoPhosTAC was able epidermal growth factor receptor (EGFR), tau, α-synuclein. Furthermore, togoPhosTAC-mediated tau dephosphorylation also correlates with reduced aggregation. sum, our hybrid biologic adaptor strategy bypassed challenges ligand development provided alternative generalizable solution precise modulation in cellulo.

Language: Английский

Citations

0
PROTAC Technology as a New Tool for Modern Pharmacotherapy DOI Creative Commons

Natalia Kubryń,

Łukasz Fijałkowski, Jacek Nowaczyk

et al.

Molecules, Journal Year: 2025, Volume and Issue: 30(10), P. 2123 - 2123

Published: May 11, 2025

The publication focuses on the innovative applications of PROTAC (proteolysis-targeting chimera) technology in modern pharmacotherapy, with particular emphasis cancer treatment. PROTACs represent an advanced therapeutic strategy that enables selective protein degradation, opening new possibilities drug design. This shows potential treatment cancers, viral infections (such as HIV and COVID-19), chronic diseases including atherosclerosis, Alzheimer’s disease, atopic dermatitis, Huntington’s disease. Promising results from clinical studies compound ARV-471 confirm effectiveness this approach. New types PROTACs, like TF-PROTAC PhosphoTAC, are designed to enhance effectiveness, stability, absorption drugs. conclusions review highlight broad various their relevance for future therapies, particularly oncology.

Language: Английский

Citations

0
SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action DOI
Yonglan Liu, Hyunbum Jang, Ruth Nussinov

et al.

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(21), P. 5175 - 5187

Published: May 15, 2024

SHP2 is a positive regulator of the EGFR-dependent Ras/MAPK pathway. It dephosphorylates regulatory phosphorylation site in EGFR that serves as binding to RasGAP (RASA1 or p120RasGAP). RASA1 activated by phosphate group. Active deactivates Ras hydrolyzing Ras-bound GTP GDP. Thus, dephosphorylation effectively prevents RASA1-mediated deactivation Ras, thereby stimulating proliferation. Despite knowledge this vital regulation cell life, mechanistic in-depth structural understanding involvement SHP2, EGFR, and pathway has largely remained elusive. Here we elucidate interactions, factors influencing EGFR's recruitment RASA1, SHP2's recognition substrate EGFR. We reveal specifically interacts with DEpY

Language: Английский

Citations

3
Modulating Phosphorylation by Proximity-Inducing Modalities for Cancer Therapy DOI
Qiuyue Zhang, Jia Yu, Qidong You

et al.

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

Published: Dec. 9, 2024

Abnormal phosphorylation of proteins can lead to various diseases, particularly cancer. Therefore, the development small molecules for precise regulation protein holds great potential drug design. While traditional kinase/phosphatase small-molecule modulators have shown some success, achieving has proven be challenging. The emergence heterobifunctional molecules, such as phosphorylation-inducing chimeric (PHICSs) and phosphatase recruiting chimeras (PHORCs), with proximity-inducing modalities is expected a breakthrough by specifically kinase or interest. Herein, we summarize targets aberrant in cancer underscore correcting therapy. Through reported cases targeting regulation, highlight current design strategies features these molecules. We also provide systematic elaboration link between aberrantly phosphorylated well existing challenges future research directions developing molecular drugs regulation.

Language: Английский

Citations

3
Roles of posttranslational modifications in lipid metabolism and cancer progression DOI Creative Commons

Tianyu Feng,

He Zhang, Yanjie Zhou

et al.

Biomarker Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: Nov. 18, 2024

Abstract Lipid metabolism reprogramming has emerged as a hallmark of malignant tumors. Lipids represent complex group biomolecules that not only compose the essential components biological membranes and act an energy source, but also function messengers to integrate various signaling pathways. In tumor cells, de novo lipogenesis plays crucial role in acquiring lipids meet demands rapid growth. Increasing evidence suggested dysregulated lipid serves driver cancer progression. Posttranslational modifications (PTMs), which occurs most eukaryotic proteins throughout their lifetimes, affect activity, abundance, function, localization, interactions target proteins. PTMs molecules are potential intervention sites emerging promising strategies for treatment. However, there is limited information available regarding occur treatment associated with these PTMs. Herein, we summarize current knowledge roles regulatory mechanisms metabolism. Understanding could provide valuable insights into tumorigenesis Moreover, targeting might novel therapeutic strategy.

Language: Английский

Citations

0
Dual-Action Kinase Inhibitors Control p38α MAP Kinase Threonine Dephosphorylation DOI Creative Commons
Emily Jane Stadnicki, Hannes Ludewig, Ramasamy P. Kumar

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 15, 2024

Abstract Reversible protein phosphorylation directs essential cellular processes including cell division, growth, death, inflammation, and differentiation. Because drives diverse diseases, kinases phosphatases have been targets for drug discovery, with some achieving remarkable clinical success. Most are activated by of their activation loops, which shifts the conformational equilibrium kinase towards active state. To turn off kinase, dephosphorylate these sites, but how conformation dynamic loop contributes to dephosphorylation was not known. answer this, we modulated human p38α MAP existing inhibitors that bind stabilize specific inactive conformations. From discovered three increase rate phospho-threonine PPM serine/threonine phosphatase WIP1. Hence, compounds “dual-action” simultaneously block site stimulate dephosphorylation. Our X-ray crystal structures phosphorylated bound dual-action reveal a shared flipped fully accessible phospho-threonine. In contrast, our structure apo reveals different an inaccessible phospho-threonine, thereby explaining increased upon inhibitor binding. These findings preference suggest new approach improved potency specificity therapeutic inhibitors.

Language: Английский

Citations

0
An Extensive Atlas of Proteome and Phosphoproteome Turnover Across Mouse Tissues and Brain Regions DOI Creative Commons
Wenxue Li, Abhijit Dasgupta, Ka Yang

et al.

Published: Oct. 17, 2024

SUMMARY Understanding how proteins in different mammalian tissues are regulated is central to biology. Protein abundance, turnover, and post-translational modifications like phosphorylation, key factors that determine tissue-specific proteome properties. However, these properties challenging study across remain poorly understood. Here, we present Turnover-PPT , a comprehensive resource mapping the abundance lifetime of 11,000 40,000 phosphosites eight mouse various brain regions, using advanced proteomics stable isotope labeling. We revealed short- long-lived proteins, strong correlations between interacting protein lifetimes, distinct impacts phosphorylation on turnover. Notably, discovered peroxisomes by turnover tissues, regulates stability neurodegeneration-related such as Tau α-synuclein. Thus, provides new fundamental insights into stability, tissue dynamic proteotypes, role accessible via an interactive web-based portal at https://yslproteomics.shinyapps.io/tissuePPT .

Language: Английский

Citations

0