Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors

Joanne Tan,Diego B Diaz,Shinya Adachi,Andrei K Yudin,Kenneth M Lum,Armand B Cognetta Iii,Soumajit Kundu,Benjamin F Cravatt

doi:10.1038/s41467-017-01319-4

Joanne Tan, Diego B Diaz + Show 6 more

Open Access

https://doi.org/10.1038/s41467-017-01319-4

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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.

Highlights

Heteroatom-rich organoboron compounds have attracted attention as modulators of enzyme function
Akin to all molecules designed to interact with protein targets, the structures of bioactive Boron-containing molecules (BCMs) must contain a sizable proportion of heteroatoms, including nitrogen, oxygen, halogens, and sulfur
For the design of small heteroatom-rich BCMs, we wanted to ensure that the parent scaffolds featuring mainly hydrogens off the connecting chain could be perturbed by the smallest possible carbon substituent capable of productive interactions with proteins

Summary

Introduction

Heteroatom-rich organoboron compounds have attracted attention as modulators of enzyme function. We have identified selective and cell-active inhibitors of the (ox)lipid-metabolizing enzyme α/β-hydrolase domain 3 (ABHD3). We assessed boronate compounds against a broad set of mammalian SHs by competitive activity-based protein profiling (ABPP) in mouse brain proteome[37].

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