7ovi
From Proteopedia
(Difference between revisions)
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High-throughput nanomole-scale synthesis allows for late-stage functionalization (LSF) of compounds in an efficient and economical manner. Here, we demonstrated that copper-catalyzed azide-alkyne cycloaddition could be used for the LSF of covalent kinase inhibitors at the nanoscale, enabling the synthesis of hundreds of compounds that did not require purification for biological assay screening, thus reducing experimental time drastically. We generated crude libraries of inhibitors for the kinase MKK7, derived from two different parental precursors, and analyzed them via the high-throughput In-Cell Western assay. Select inhibitors were resynthesized, validated via conventional biological and biochemical methods such as western blots and liquid chromatography-mass spectrometry (LC-MS) labeling, and successfully co-crystallized. Two of these compounds showed over 20-fold increased inhibitory activity compared to the parental compound. This study demonstrates that high-throughput LSF of covalent inhibitors at the nanomole-scale level can be an auspicious approach in improving the properties of lead chemical matter. | High-throughput nanomole-scale synthesis allows for late-stage functionalization (LSF) of compounds in an efficient and economical manner. Here, we demonstrated that copper-catalyzed azide-alkyne cycloaddition could be used for the LSF of covalent kinase inhibitors at the nanoscale, enabling the synthesis of hundreds of compounds that did not require purification for biological assay screening, thus reducing experimental time drastically. We generated crude libraries of inhibitors for the kinase MKK7, derived from two different parental precursors, and analyzed them via the high-throughput In-Cell Western assay. Select inhibitors were resynthesized, validated via conventional biological and biochemical methods such as western blots and liquid chromatography-mass spectrometry (LC-MS) labeling, and successfully co-crystallized. Two of these compounds showed over 20-fold increased inhibitory activity compared to the parental compound. This study demonstrates that high-throughput LSF of covalent inhibitors at the nanomole-scale level can be an auspicious approach in improving the properties of lead chemical matter. | ||
| - | Optimization of Covalent MKK7 Inhibitors via Crude Nanomole-Scale Libraries.,Gehrtz P, Marom S, Buhrmann M, Hardick J, Kleinbolting S, Shraga A, Dubiella C, Gabizon R, Wiese JN, Muller MP, Cohen G, Babaev I, Shurrush K, Avram L, Resnick E, Barr H, Rauh D, London N J Med Chem. 2022 | + | Optimization of Covalent MKK7 Inhibitors via Crude Nanomole-Scale Libraries.,Gehrtz P, Marom S, Buhrmann M, Hardick J, Kleinbolting S, Shraga A, Dubiella C, Gabizon R, Wiese JN, Muller MP, Cohen G, Babaev I, Shurrush K, Avram L, Resnick E, Barr H, Rauh D, London N J Med Chem. 2022 Aug 11;65(15):10341-10356. doi: 10.1021/acs.jmedchem.1c02206. , Epub 2022 Jul 30. PMID:35912476<ref>PMID:35912476</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
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[[Category: Mueller MP]] | [[Category: Mueller MP]] | ||
[[Category: Rauh D]] | [[Category: Rauh D]] | ||
| - | [[Category: Wiese JN]] | ||
Current revision
Protein kinase MKK7 in complex with phenethyltriazole-substituted pyrazolopyrimidine
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