Protein kinases comprise a large family of structurally related enzymes. A major goal in kinase-inhibitor development is to selectively engage the desired kinase while avoiding myriad off-target kinases. However, quantifying inhibitor interactions with multiple endogenous kinases in live cells remains an unmet challenge. Here, we report the design of sulfonyl fluoride probes that covalently label a broad swath of the intracellular kinome with high efficiency. Protein crystallography and mass spectrometry confirmed a chemoselective reaction between the sulfonyl fluoride and a conserved lysine in the ATP binding site. Optimized probe 2 (XO44) covalently modified up to 133 endogenous kinases, efficiently competing with high intracellular concentrations of ATP. We employed probe 2 and label-free mass spectrometry to quantify intracellular kinase engagement by the approved drug, dasatinib. The data revealed saturable dasatinib binding to a small subset of kinase targets at clinically relevant concentrations, highlighting the utility of lysine-targeted sulfonyl fluoride probes in demanding chemoproteomic applications.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858558 | PMC |
| http://dx.doi.org/10.1021/jacs.6b08536 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The European Commission requested the EFSA Panel on Plant Health to deliver a risk assessment on the likelihood of pest freedom from regulated EU quarantine pests, with emphasis on and its vectors spp. of debarked conifer wood chips fumigated with sulfuryl fluoride as proposed by the United States (US) and as outlined in ISPM 28 - PT23 of sulfuryl fluoride (SF) fumigation treatment for nematodes and insects in debarked wood. The assessment considered the different phases in the wood chips' production, with special emphasis on the SF treatment.
View Article and Find Full Text PDFEngineering Covalent Aptamer Chimeras for Enhanced Autophagic Degradation of Membrane Proteins.
Angew Chem Int Ed Engl
January 2025
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China.
Targeted degradation of membrane proteins represents an attractive strategy for eliminating pathogenesis-related proteins. Aptamer-based chimeras hold great promise as membrane protein degraders, however, their degradation efficacy is often hindered by the limited structural stability and the risk of off-target effects due to the non-covalent interaction with target proteins. We here report the first design of a covalent aptamer-based autophagosome-tethering chimera (CApTEC) for the enhanced autophagic degradation of cell-surface proteins, including transferrin receptor 1 (TfR1) and nucleolin (NCL).
View Article and Find Full Text PDFUnveiling the cyclopropyl appended acyl thiourea derivatives as antimicrobial, α-amylase and proteinase K inhibitors: Design, synthesis, biological evaluation, molecular docking, DFT and ADMET studies.
Arch Biochem Biophys
January 2025
Department of Biosciences Grand Asian University of Sialkot, Pakistan.
Acyl thiourea scaffolds are frequently employed in drug development to discern unique and essential therapies for the eradication of the most challenging diseases. Hence, we developed a library of novel cyclopropyl incorporating acyl thiourea derivatives (4a-j) and evaluated their antimicrobial, α-amylase, and proteinase K inhibition potential. Compound (4h) (4-methoxy) demonstrated the strongest α-amylase inhibition (IC = 1.
View Article and Find Full Text PDFThe Synthesis of Sulfonyl Fluoride Functionalized 2-Aminothiazoles Using a Diversity Oriented Clicking Strategy.
Org Lett
December 2024
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
We present a Diversity Oriented Clicking approach to synthesize a library of novel clickable -substituted 2-aminothiazoles which serve as versatile hubs for SuFEx click chemistry diversification. Leveraging the spring-loaded reactivity of the 2-Substituted-Alkynyl-1-Sulfonyl Fluoride (SASF) connectors, the transformation is simple to perform, tolerant of a wide range of functionality, and regioselective for a single product. Finally, we propose a detailed stepwise reaction mechanism that is supported by experimental and computational analysis.
View Article and Find Full Text PDFCatalytic Lysine745 targeting strategy in fourth-generation EGFR tyrosine kinase inhibitors to address C797S mutation resistance.
Eur J Med Chem
February 2025
R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, 425405, Maharashtra, India. Electronic address:
Overcoming resistance to third-generation tyrosine kinase inhibitors (TKIs) such as Osimertinib, particularly due to the emergence of the C797S mutation, remains a key challenge in non-small cell lung cancer (NSCLC) therapy. This review highlights recent advancements in the development of fourth-generation EGFR inhibitors that specifically target the catalytic Lys745 residue, aiming to overcome resistance associated with Osimertinib. Both covalent and non-covalent inhibitors targeting Lys745 were explored, using warheads like sulfonyl fluoride, phosphine oxides, esters, and trisubstituted imidazoles.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!