Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors

Joanne Tan, Armand B. Cognetta, Diego B. Diaz, Kenneth M. Lum, Shinya Adachi, Soumajit Kundu, Benjamin F. Cravatt and Andrei K. Yudin ()
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Joanne Tan: University of Toronto
Armand B. Cognetta: The Skaggs Institute for Chemical Biology, The Scripps Research Institute
Diego B. Diaz: University of Toronto
Kenneth M. Lum: The Skaggs Institute for Chemical Biology, The Scripps Research Institute
Shinya Adachi: University of Toronto
Soumajit Kundu: The Skaggs Institute for Chemical Biology, The Scripps Research Institute
Benjamin F. Cravatt: The Skaggs Institute for Chemical Biology, The Scripps Research Institute
Andrei K. Yudin: University of Toronto

Nature Communications, 2017, vol. 8, issue 1, 1-8

Abstract: Abstract 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 IC50 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.

Date: 2017
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DOI: 10.1038/s41467-017-01319-4

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