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Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors

Heteroatom-rich organoboron compounds have attracted attention as modulators of enzyme function. Driven by the unmet need to develop chemoselective access to boron chemotypes, we report herein the synthesis of α- and β-aminocyano(MIDA)boronates from borylated carbonyl compounds. Activity-based prote...

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Autores principales: Tan, Joanne, Cognetta III, Armand B., Diaz, Diego B., Lum, Kenneth M., Adachi, Shinya, Kundu, Soumajit, Cravatt, Benjamin F., Yudin, Andrei K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701053/
https://www.ncbi.nlm.nih.gov/pubmed/29170371
http://dx.doi.org/10.1038/s41467-017-01319-4
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author Tan, Joanne
Cognetta III, Armand B.
Diaz, Diego B.
Lum, Kenneth M.
Adachi, Shinya
Kundu, Soumajit
Cravatt, Benjamin F.
Yudin, Andrei K.
author_facet Tan, Joanne
Cognetta III, Armand B.
Diaz, Diego B.
Lum, Kenneth M.
Adachi, Shinya
Kundu, Soumajit
Cravatt, Benjamin F.
Yudin, Andrei K.
author_sort Tan, Joanne
collection PubMed
description Heteroatom-rich organoboron compounds have attracted attention as modulators of enzyme function. Driven by the unmet need to develop chemoselective access to boron chemotypes, we report herein the synthesis of α- and β-aminocyano(MIDA)boronates from borylated carbonyl compounds. Activity-based protein profiling of the resulting β-aminoboronic acids furnishes selective and cell-active inhibitors of the (ox)lipid-metabolizing enzyme α/β-hydrolase domain 3 (ABHD3). The most potent compound displays nanomolar in vitro and in situ IC(50) values and fully inhibits ABHD3 activity in human cells with no detectable cross-reactivity against other serine hydrolases. These findings demonstrate that synthetic methods that enhance the heteroatom diversity of boron-containing molecules within a limited set of scaffolds accelerate the discovery of chemical probes of human enzymes.
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spelling pubmed-57010532017-11-27 Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors Tan, Joanne Cognetta III, Armand B. Diaz, Diego B. Lum, Kenneth M. Adachi, Shinya Kundu, Soumajit Cravatt, Benjamin F. Yudin, Andrei K. Nat Commun Article Heteroatom-rich organoboron compounds have attracted attention as modulators of enzyme function. Driven by the unmet need to develop chemoselective access to boron chemotypes, we report herein the synthesis of α- and β-aminocyano(MIDA)boronates from borylated carbonyl compounds. Activity-based protein profiling of the resulting β-aminoboronic acids furnishes selective and cell-active inhibitors of the (ox)lipid-metabolizing enzyme α/β-hydrolase domain 3 (ABHD3). The most potent compound displays nanomolar in vitro and in situ IC(50) values and fully inhibits ABHD3 activity in human cells with no detectable cross-reactivity against other serine hydrolases. These findings demonstrate that synthetic methods that enhance the heteroatom diversity of boron-containing molecules within a limited set of scaffolds accelerate the discovery of chemical probes of human enzymes. Nature Publishing Group UK 2017-11-24 /pmc/articles/PMC5701053/ /pubmed/29170371 http://dx.doi.org/10.1038/s41467-017-01319-4 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Tan, Joanne
Cognetta III, Armand B.
Diaz, Diego B.
Lum, Kenneth M.
Adachi, Shinya
Kundu, Soumajit
Cravatt, Benjamin F.
Yudin, Andrei K.
Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors
title Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors
title_full Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors
title_fullStr Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors
title_full_unstemmed Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors
title_short Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors
title_sort multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701053/
https://www.ncbi.nlm.nih.gov/pubmed/29170371
http://dx.doi.org/10.1038/s41467-017-01319-4
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