scholarly journals Multiplex Imaging and Cellular Target Identification of Kinase Inhibitors via an Affinity-Based Proteome Profiling Approach

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Ying Su ◽  
Sijun Pan ◽  
Zhengqiu Li ◽  
Lin Li ◽  
Xiaoyuan Wu ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Target Identification ◽  
Proteome Profiling ◽  
Cellular Target

Drug Target Identification in Tissues by Thermal Proteome Profiling

2021 ◽  
Vol 62 (1) ◽  
Author(s):  
André Mateus ◽  
Nils Kurzawa ◽  
Jessica Perrin ◽  
Giovanna Bergamini ◽  
Mikhail M. Savitski
Keyword(s):  
Drug Target ◽  
Target Identification ◽  
Annual Review ◽  
Publication Date ◽  
Proteome Profiling ◽  
Biological Phenomena ◽  
Target Deconvolution ◽  
Drug Target Identification ◽  
Recent Developments ◽  
Fundamental Biology

Drug target deconvolution can accelerate the drug discovery process by identifying a drug's targets (facilitating medicinal chemistry efforts) and off-targets (anticipating toxicity effects or adverse drug reactions). Multiple mass spectrometry–based approaches have been developed for this purpose, but thermal proteome profiling (TPP) remains to date the only one that does not require compound modification and can be used to identify intracellular targets in living cells. TPP is based on the principle that the thermal stability of a protein can be affected by its interactions. Recent developments of this approach have expanded its applications beyond drugs and cell cultures to studying protein-drug interactions and biological phenomena in tissues. These developments open up the possibility of studying drug treatment or mechanisms of disease in a holistic fashion, which can result in the design of better drugs and lead to a better understanding of fundamental biology. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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.

scholarly journals A Focused Small-Molecule Screen Identifies 14 Compounds with Distinct Effects on Toxoplasma gondii

2012 ◽  
Vol 56 (11) ◽  
pp. 5581-5590 ◽  
Author(s):  
Edwin T. Kamau ◽  
Ananth R. Srinivasan ◽  
Mark J. Brown ◽  
Matthew G. Fair ◽  
Erin J. Caraher ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Host Cell ◽  
Kinase Inhibitors ◽  
Severe Disease ◽  
Content Type ◽  
Cellular Target ◽  
Small Molecule Screen ◽  
Parasite Motility ◽  
Future Work

ABSTRACTToxoplasma gondiiis a globally ubiquitous pathogen that can cause severe disease in immunocompromised humans and the developing fetus. Given the proven role ofToxoplasma-secreted kinases in the interaction ofToxoplasmawith its host cell, identification of novel kinase inhibitors could precipitate the development of new anti-Toxoplasmadrugs and define new pathways important for parasite survival. We selected a small (n= 527) but diverse set of putative kinase inhibitors and screened them for effects on the growth ofToxoplasmain vitro. We identified and validated 14 noncytotoxic compounds, all of which had 50% effective concentrations in the nanomolar to micromolar range. We further characterized eight of these compounds, four inhibitors and four enhancers, by determining their effects on parasite motility, invasion, and the likely cellular target (parasite or host cell). Only two compounds had an effect on parasite motility and invasion. All the inhibitors appeared to target the parasite, and interestingly, two of the enhancers appeared to rather target the host cell, suggesting modulation of host cell pathways beneficial for parasite growth. For the four inhibitors, we also tested their efficacy in a mouse model, where one compound proved potent. Overall, these 14 compounds represent a new and diverse set of small molecules that are likely targeting distinct parasite and host cell pathways. Future work will aim to characterize their molecular targets in both the host and parasite.

Design and Synthesis of Minimalist Terminal Alkyne-Containing Diazirine Photo-Crosslinkers and Their Incorporation into Kinase Inhibitors for Cell- and Tissue-Based Proteome Profiling

2013 ◽  
Vol 52 (33) ◽  
pp. 8551-8556 ◽  
Author(s):  
Zhengqiu Li ◽  
Piliang Hao ◽  
Lin Li ◽  
Chelsea Y. J. Tan ◽  
Xiamin Cheng ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Terminal Alkyne ◽  
Proteome Profiling ◽  
Design And Synthesis

Target identification, lead optimization and antitumor evaluation of some new 1,2,4-triazines as c-Met kinase inhibitors

2017 ◽  
Vol 73 ◽  
pp. 154-169 ◽  
Author(s):  
Marwa H. El-Wakil ◽  
Hayam M. Ashour ◽  
Manal N. Saudi ◽  
Ahmed M. Hassan ◽  
Ibrahim M. Labouta
Keyword(s):  
Kinase Inhibitors ◽  
Target Identification ◽  
Lead Optimization ◽  
Antitumor Evaluation

Design and Synthesis of Minimalist Terminal Alkyne-Containing Diazirine Photo-Crosslinkers and Their Incorporation into Kinase Inhibitors for Cell- and Tissue-Based Proteome Profiling

2013 ◽  
Vol 125 (33) ◽  
pp. 8713-8718 ◽  
Author(s):  
Zhengqiu Li ◽  
Piliang Hao ◽  
Lin Li ◽  
Chelsea Y. J. Tan ◽  
Xiamin Cheng ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Terminal Alkyne ◽  
Proteome Profiling ◽  
Design And Synthesis

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 Developments of bioorthogonal handle-containing photo-crosslinkers for photoaffinity labeling

MedChemComm ◽  
2017 ◽  
Vol 8 (8) ◽  
pp. 1585-1591 ◽  
Author(s):  
Haijun Guo ◽  
Zhengqiu Li
Keyword(s):  
Small Molecules ◽  
Target Identification ◽  
Photoaffinity Labeling ◽  
Proteome Profiling

“Minimalist” photo-crosslinkers (L3–L6) applied in affinity-based proteome profiling and bioimaging for target identification of small molecules.

scholarly journals Label-Free Proteome Profiling as a Quantitative Target Identification Technique for Bioactive Small Molecules

Biochemistry ◽  
2019 ◽  
Vol 59 (3) ◽  
pp. 213-215
Author(s):  
Kyung Tae Hong ◽  
Jun-Seok Lee
Keyword(s):  
Small Molecules ◽  
Target Identification ◽  
Label Free ◽  
Proteome Profiling ◽  
Identification Technique

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.

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