Mapping Protein Targets of Bioactive Small Molecules Using Lipid-Based Chemical Proteomics

Lum, Kenneth M.; Sato, Yoshiaki; Beyer, Brittney A.; Plaisted, Warren C.; Anglin, Justin L.; Lairson, Luke L.; Cravatt, Benjamin F.

doi:10.1021/acschembio.7b00581

Cited by 25 publications

(22 citation statements)

References 55 publications

(209 reference statements)

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“…50 The 1,5-benzothiazepine derivatives also exhibited various important biological activities. [51][52][53][54][55] As shown in Scheme 7B, in the presence of Cu(OTf) 2 under air, dearomatized cycloadduct 3q was smoothly converted to 1,5-benzothiazepine derivative 10 in 93% yield and 95% ee. The structure of 1,5-benzothiazepine 10 was also confirmed by single-crystal X-ray diffraction analysis.…”

Section: Resultsmentioning

confidence: 99%

Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Aminocyclopropanes

Zhang

Wang

Xie

et al. 2019

Chem

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The enantioselective dearomative [3 + 2] cycloaddition reaction of benzazoles with aminocyclopropanes has been successfully developed. In the presence of a copper complex, derived from Cu(OTf) 2 and bisoxazoline, a series of hydropyrrolo-benzazole derivatives containing quaternary stereogenic centers were obtained in high yields with excellent enantioselectivity. This method could also provide 2-amino cyclopropanes with high enantiomeric purity by an efficient kinetic resolution. In addition, products could be transformed to pyrrolobenzothiazines and 1,5-benzothiazepines.

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Section: Resultsmentioning

confidence: 99%

Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Aminocyclopropanes

Zhang

Wang

Xie

et al. 2019

Chem

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“…S1P lyase activity was assayed essentially as described previously 43 . Briefly, HEK293T cells overexpressing FLAG-tagged human S1P lyase were lysed by sonication (Diagenode Bioruptor; 5 × 30 s cycles) on ice into 50 mM HEPES buffer (pH 7.5) containing 25 µM Na 3 VO 4 and complete protease inhibitors (Roche).…”

Section: Methodsmentioning

confidence: 99%

The sphingosine 1-phosphate receptor 2/4 antagonist JTE-013 elicits off-target effects on sphingolipid metabolism

Pitman

Lewis

Davies

et al. 2022

Sci Rep

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Sphingosine 1-phosphate (S1P) is a signaling lipid that has broad roles, working either intracellularly through various protein targets, or extracellularly via a family of five G-protein coupled receptors. Agents that selectively and specifically target each of the S1P receptors have been sought as both biological tools and potential therapeutics. JTE-013, a small molecule antagonist of S1P receptors 2 and 4 (S1P2 and S1P4) has been widely used in defining the roles of these receptors in various biological processes. Indeed, our previous studies showed that JTE-013 had anti-acute myeloid leukaemia (AML) activity, supporting a role for S1P2 in the biology and therapeutic targeting of AML. Here we examined this further and describe lipidomic analysis of AML cells that revealed JTE-013 caused alterations in sphingolipid metabolism, increasing cellular ceramides, dihydroceramides, sphingosine and dihydrosphingosine. Further examination of the mechanisms behind these observations showed that JTE-013, at concentrations frequently used in the literature to target S1P2/4, inhibits several sphingolipid metabolic enzymes, including dihydroceramide desaturase 1 and both sphingosine kinases. Collectively, these findings demonstrate that JTE-013 can have broad off-target effects on sphingolipid metabolism and highlight that caution must be employed in interpreting the use of this reagent in defining the roles of S1P2/4.

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“…Along these lines, combination of chemical proteomics with fragment‐based ligand discovery was established as a platform to map interactions of small molecules and proteins in human cells . Last but not least, chemical proteomics approach has been used to assess lipid–protein interactions …”

Section: Chemical Proteomics For Drug Selectivity and Inhibitor Bindingmentioning

confidence: 99%

Proteomics in Drug Development: The Dawn of a New Era?

Frantzi

Latosinska

Mischak

2019

Proteomics Clinical Apps

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Mass spectrometry offers the potential of acquiring high resolution data depicting the functional status of a group of healthy or diseased individuals, according to different conditions. As most of the drugs are currently targeting proteins, proteomics has a dual value, both in the discovery of new molecules as therapeutic targets, but also as a methodology to perform high throughput drug profiling. As there is an evident need for drugs to be improved in terms of efficacy, a mechanistic insight for downstream effectors can be valuable in order to predict side effects and resistance mechanisms. Recently developed assays, like thermal proteome profiling enables comprehensive drug target profiling and is, therefore, of high value in drug discovery. In this review, a systematic literature search is conducted and the most prominent proteomics studies as implicated in assisting drug discovery and development is presented. Focus is placed on investigations that are closer to implementation, therefore particular emphasis is given in studies conducted in human diseased population and further verified in vitro or in vivo.

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Mapping Protein Targets of Bioactive Small Molecules Using Lipid-Based Chemical Proteomics

Cited by 25 publications

References 55 publications

Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Aminocyclopropanes

Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Aminocyclopropanes

The sphingosine 1-phosphate receptor 2/4 antagonist JTE-013 elicits off-target effects on sphingolipid metabolism

Proteomics in Drug Development: The Dawn of a New Era?

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