An update on small molecule compounds targeting synthetic lethality for cancer therapy DOI
Jiaxiang Luo, Yang Li, Yiwen Zhang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 278, P. 116804 - 116804

Published: Sept. 2, 2024

Language: Английский

Robust proteome profiling of cysteine-reactive fragments using label-free chemoproteomics DOI Creative Commons
George S. Biggs, Emma E. Cawood, Aini Vuorinen

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Abstract Identifying pharmacological probes for human proteins represents a key opportunity to accelerate the discovery of new therapeutics. High-content screening approaches expand ligandable proteome offer potential expedite novel chemical study protein function. Screening libraries reactive fragments by chemoproteomics offers compelling approach ligand discovery, however, optimising sample throughput, proteomic depth, and data reproducibility remains challenge. We report versatile, label-free quantification proteomics platform competitive profiling cysteine-reactive against native proteome. This high-throughput combines SP4 plate-based preparation with rapid chromatographic gradients. Data-independent acquisition performed on Bruker timsTOF Pro 2 consistently identified ~23,000 cysteine sites per run, total ~32,000 profiled in HEK293T Jurkat lysate. Crucially, this depth cysteinome coverage is met high completeness, enabling robust identification liganded proteins. In study, 80 were screened two cell lines identifying >400 ligand-protein interactions. Hits validated through concentration-response experiments was utilised hit expansion live experiments. significant step forward evaluate ligandability cysteines across

Language: Английский

Citations

4
Structural Chemistry of Helicase Inhibition DOI Creative Commons

Lakshi Selvaratnam,

Timothy M. Willson, Matthieu Schapira

et al.

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

Published: Feb. 11, 2025

Helicases are essential motor enzymes that couple nucleoside-triphosphate hydrolysis with DNA or RNA strand unwinding. integral to replication, transcription, splicing, and translation of the genome, play crucial roles in proliferation cancer cells propagation viral pathogens, implicated neurodegenerative diseases. Despite their therapeutic potential, drug discovery efforts targeting helicases face significant challenges due dynamic enzymatic cycles, transient nature conformational states, conservation active sites. Analysis cocrystal structures inhibitor–helicase complexes revealed four distinct mechanisms inhibition: allosteric, ATP-competitive, RNA-competitive, interfacial inhibitors. While these static X-ray reveal potential binding pockets may support development selective drugs, application advanced techniques such as cryo-EM, single-molecule analysis, computational modeling will be for understanding helicase dynamics designing effective

Language: Английский

Citations

2
Discovery of novel WRN inhibitors for treating MSI-H colorectal cancers DOI Creative Commons
Byul Moon,

Ahra Go,

Seulki Park

et al.

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown, P. 130141 - 130141

Published: Feb. 1, 2025

Language: Английский

Citations

1
Recent Advances in Mass Spectrometry-Based Bottom-Up Proteomics DOI
Cameron S. Movassaghi, Jie Sun, Yuming Jiang

et al.

Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

Mass spectrometry-based proteomics is about 35 years old, and recent progress appears to be speeding up across all subfields. In this review, we focus on advances over the last two in select areas within bottom-up proteomics, including approaches high-throughput experiments, data analysis using machine learning, drug discovery, glycoproteomics, extracellular vesicle structural proteomics.

Language: Английский

Citations

1
A covalent chemical probe for Chikungunya nsP2 cysteine protease with antialphaviral activity and proteome-wide selectivity DOI Creative Commons
Anirban Ghoshal, Edwin G. Tse, Mohammad Anwar Hossain

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 1, 2025

Language: Английский

Citations

1
Oncological characteristics, treatments and prognostic outcomes in MMR-deficient colorectal cancer DOI Creative Commons

Wenxuan Fan,

Fei Su, Yan Zhang

et al.

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

Published: Aug. 26, 2024

Abstract Colorectal cancer (CRC) ranks as the third most prevalent globally. It’s recognized that molecular subtype of CRC, characterized by mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H), plays a critical role in determining appropriate treatment strategies. This review examines current classifications, focusing on dMMR/MSI-H CRC and its subtypes: Lynch syndrome (LS), Lynch-like (LLS), sporadic cases. Despite advances understanding these genetic backgrounds, clinical trials have not conclusively differentiated efficacy immune checkpoint inhibitors among subgroups. Therefore, while this details characteristics their general implications for prognosis, it also highlights limitations need more refined studies to ascertain tailored therapeutic strategies each subtype. Furthermore, summarizes completed ongoing studies, emphasizing importance developing treatments aligned closely with profiles. By discussing aspects, seeks provide comprehensive analysis oncological characteristics, presenting detailed prognosis CRC.

Language: Английский

Citations

7
Covalent Inhibitors: To Infinity and Beyond DOI
Yasir S. Raouf

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(13), P. 10513 - 10516

Published: June 24, 2024

ADVERTISEMENT RETURN TO ARTICLES ASAPPREVEditorialNEXTCovalent Inhibitors: To Infinity and BeyondYasir S. Raouf*Yasir RaoufDepartment of Chemistry, College Science, United Arab Emirates University, Al Ain 15551, UAE*[email protected]More by Yasir Raoufhttps://orcid.org/0000-0001-5142-8056Cite this: J. Med. Chem. 2024, XXXX, XXX, XXX-XXXPublication Date (Web):June 24, 2024Publication History Received9 June 2024Published online24 2024https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01308https://doi.org/10.1021/acs.jmedchem.4c01308editorialACS PublicationsPublished 2024 American Chemical Society. This publication is available under these Terms Use. Request reuse permissions free to access through this site. Learn MoreArticle Views-Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum full text article downloads since November 2008 (both PDF HTML) across all institutions individuals. These metrics regularly updated reflect usage leading up last few days.Citations number other articles citing article, calculated Crossref daily. Find more information about citation counts.The Altmetric Attention Score a quantitative measure attention that research has received online. Clicking on donut icon will load page at altmetric.com with additional details score social media presence for given article. how calculated. Share Add toView InAdd Full Text ReferenceAdd Description ExportRISCitationCitation abstractCitation referencesMore Options onFacebookTwitterWechatLinked InRedditEmail (787 KB) Get e-AlertscloseSUBJECTS:Cancer,Drug discovery,Electrophiles,Inhibitors,Molecules e-Alerts

Language: Английский

Citations

6
Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of Chikungunya nsP2 Cysteine Protease with Antialphavirus Activity DOI Creative Commons
Anirban Ghoshal, Kesatebrhan Haile Asressu, Mohammad Anwar Hossain

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(18), P. 16505 - 16532

Published: Sept. 5, 2024

Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 (

Language: Английский

Citations

6
Ligand discovery by activity-based protein profiling DOI
Micah J. Niphakis, Benjamin F. Cravatt

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(9), P. 1636 - 1651

Published: Sept. 1, 2024

Language: Английский

Citations

6
Structure-based discovery of first inhibitors targeting the helicase activity of human PIF1 DOI Creative Commons

Mark Jacobus Anthonius Wever,

Francesca R Scommegna,

Sara Egea‐Rodriguez

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(20), P. 12616 - 12632

Published: Sept. 30, 2024

PIF1 is a conserved helicase and G4 DNA binding unwinding enzyme, with roles in genome stability. Human (hPIF1) poorly understood, but its functions can become critical for tumour cell survival during oncogene-driven replication stress. Here we report the discovery, via an X-ray crystallographic fragment screen (XChem), of hPIF1 inhibitors. A structure was obtained 4-phenylthiazol-2-amine bound pocket between domains 2A 2B, additional contacts to Valine 258 from domain 1A. The compound makes specific interactions, notably through Leucine 548 Alanine 551, that constrain conformational adjustments previously linked ATP hydrolysis unwinding. We next synthesized range related compounds characterized their effects on DNA-binding activity vitro, expanding relationship (SAR) around initial hit. systematic analysis clinical cancer databases also presented here, supporting notion upregulation may represent vulnerability. research demonstrates tractable target derivatives as inhibitors action, setting foundation creation novel class anti-cancer therapeutics.

Language: Английский

Citations

5