Cellular target identification of Withangulatin A using fluorescent analogues and subsequent chemical proteomics

2019 ◽  
Vol 55 (57) ◽  
pp. 8231-8234
Author(s):  
Tianyu Zhu ◽  
Chen Chen ◽  
Sisi Wang ◽  
Yi Zhang ◽  
Dongrong Zhu ◽  
...  
Keyword(s):  
Fluorescent Probes ◽  
Target Identification ◽  
Chemical Proteomics ◽  
Cellular Target ◽  
Subsequent Chemical ◽  
Fluorescent Analogues

Find the target of Withangulatin A with the combination of fluorescent probes and chemical proteomics.

scholarly journals Development of photo-lenalidomide for cellular target identification

2021 ◽  
Author(s):  
Zhi Lin ◽  
Yuka Amako ◽  
Farah Kabir ◽  
Hope A Flaxman ◽  
Bogdan Budnik ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Target Identification ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Chemical Proteomics ◽  
Eukaryotic Translation ◽  
Site Mapping ◽  
Cellular Target ◽  
Eukaryotic Translation Initiation ◽  
Translation Initiation Factor 3

The thalidomide analog lenalidomide is a clinical therapeutic that alters the substrate engagement of cereblon (CRBN), a substrate receptor for the CRL4 E3 ubiquitin ligase. Here, we report the development of photo-lenalidomide, a lenalidomide probe with a photo-affinity label and enrichment handle, for target identification by chemical proteomics. After evaluating a series of lenalidomide analogs, we identified a specific amide linkage to lenalidomide that allowed for installation of the desired functionality, while preserving the substrate degradation profile, phenotypic anti-proliferative and immunomodulatory properties of lenalidomide. Photo-lenalidomide maintains these properties by enhancing binding interactions with the thalidomide-binding domain of CRBN, as revealed by binding site mapping and molecular modeling. Using photo-lenalidomide, we captured the known targets IKZF1 and CRBN from multiple myeloma MM.1S cells, and further identified a new target, eukaryotic translation initiation factor 3 subunit i (eIF3i), from HEK293T cells. eIF3i is directly labeled by photo-lenalidomide and forms a complex with CRBN in the presence of lenalidomide, but is itself not ubiquitylated or degraded. These data point to the potentially broader array of substrates induced by ligands to CRBN that may or may not be degraded, which can be revealed by the highly translatable application of photo-lenalidomide and chemical proteomics in additional biological settings.

scholarly journals From Phenotypic Hit to Chemical Probe: Chemical Biology Approaches to Elucidate Small Molecule Action in Complex Biological Systems

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5702
Author(s):  
Quentin T. L. Pasquer ◽  
Ioannis A. Tsakoumagkos ◽  
Sascha Hoogendoorn
Keyword(s):  
Small Molecules ◽  
Chemical Biology ◽  
Target Identification ◽  
Biologically Active ◽  
Phenotypic Screening ◽  
Biological Processes ◽  
Chemical Probes ◽  
Target Deconvolution ◽  
Cellular Target ◽  
Screening Approaches

Biologically active small molecules have a central role in drug development, and as chemical probes and tool compounds to perturb and elucidate biological processes. Small molecules can be rationally designed for a given target, or a library of molecules can be screened against a target or phenotype of interest. Especially in the case of phenotypic screening approaches, a major challenge is to translate the compound-induced phenotype into a well-defined cellular target and mode of action of the hit compound. There is no “one size fits all” approach, and recent years have seen an increase in available target deconvolution strategies, rooted in organic chemistry, proteomics, and genetics. This review provides an overview of advances in target identification and mechanism of action studies, describes the strengths and weaknesses of the different approaches, and illustrates the need for chemical biologists to integrate and expand the existing tools to increase the probability of evolving screen hits to robust chemical probes.

Target identification of natural and traditional medicines with quantitative chemical proteomics approaches

2016 ◽  
Vol 162 ◽  
pp. 10-22 ◽  
Author(s):  
Jigang Wang ◽  
Liqian Gao ◽  
Yew Mun Lee ◽  
Karunakaran A. Kalesh ◽  
Yong Siang Ong ◽  
...  
Keyword(s):  
Target Identification ◽  
Chemical Proteomics ◽  
Traditional Medicines ◽  
Quantitative Chemical

Chemical Proteomics Reveals Heat Shock Protein 60 To Be the Main Cellular Target of the Marine Bioactive Sesterterpene Suvanine

ChemBioChem ◽  
2012 ◽  
Vol 13 (13) ◽  
pp. 1953-1958 ◽  
Author(s):  
Chiara Cassiano ◽  
Maria Chiara Monti ◽  
Carmen Festa ◽  
Angela Zampella ◽  
Raffaele Riccio ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 60 ◽  
Chemical Proteomics ◽  
Cellular Target

scholarly journals Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Santanu Hati ◽  
Sayantan Tripathy ◽  
Pratip Kumar Dutta ◽  
Rahul Agarwal ◽  
Ramprasad Srinivasan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Identification ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Cellular Target

scholarly journals Chemical Proteomics Applied to Target Identification and Drug Discovery

BioTechniques ◽  
2005 ◽  
Vol 38 (2) ◽  
pp. 175-177 ◽  
Author(s):  
Steven H.L. Verhelst ◽  
Matthew Bogyo
Keyword(s):  
Drug Discovery ◽  
Target Identification ◽  
Chemical Proteomics

scholarly journals Cleavable linkers and their application in MS-based target identification

2021 ◽  
Author(s):  
Hester A. Beard ◽  
Dimitris Korovesis ◽  
Suyuan Chen ◽  
Steven H. L. Verhelst
Keyword(s):  
Mass Spectrometry ◽  
Target Identification ◽  
Chemical Proteomics

In chemical proteomics workflows, cleavable linkers are increasingly used to facilitate target identification by mass spectrometry. This review discusses the various types of cleavable linkers and their application areas.

scholarly journals Identification of PDE6D as a potential target of sorafenib via PROTAC technology

2020 ◽  
Author(s):  
Yang Li ◽  
Qingshi Meng ◽  
Ping Wang ◽  
Xiaolei Liu ◽  
Qiuyu Fu ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Kinase Inhibitor ◽  
Target Identification ◽  
Binding Interaction ◽  
Cellular Targets ◽  
Potential Target ◽  
Cellular Target ◽  
Anti Cancer ◽  
Different Types ◽  
Direct Binding

AbstractThe identification of unknown target of a multi-kinase inhibitor sorafenib is important to better understand the mechanism of action of this drug in anti-cancer and anti-fibrotic treatments. Here, we report the combination of PROTAC technique with quantitative proteomic analysis to identify the unknown cellular targets of sorafenib. Sorafenib-based PROTAC can strongly degrade a non-kinase target PDEδ in different types of cells. We also confirmed the direct binding interaction of PDEδ with sorafenib by CETSA and SPR assays. Together, our research suggests that PDEδ is a new potential target of sorafenib, and PROTAC technology may be a promising approach for cellular target identification of bioactive compounds of interest.

Sign in / Sign up

Export Citation Format

Share Document