Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry

• Published in: Journal of the American Chemical Society Vol. 142; no. 25; pp. 10899 - 10904
• Main Authors: Kitamura, Seiya, Zheng, Qinheng, Woehl, Jordan L, Solania, Angelo, Chen, Emily, Dillon, Nicholas, Hull, Mitchell V, Kotaniguchi, Miyako, Cappiello, John R, Kitamura, Shinichi, Nizet, Victor, Sharpless, K. Barry, Wolan, Dennis W
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24-06-2020
• Subjects: Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Catalytic Domain; Click Chemistry; Crystallography, X-Ray; Cysteine Proteinase Inhibitors - metabolism; Cysteine Proteinase Inhibitors - pharmacology; Cysteine Proteinase Inhibitors - toxicity; Drug Discovery; Exotoxins - antagonists & inhibitors; Exotoxins - chemistry; Exotoxins - metabolism; High-Throughput Screening Assays; Humans; Jurkat Cells; Microsomes, Liver - metabolism; Proof of Concept Study; Protein Binding; Sulfur Compounds - chemistry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.9b13652

Optimization of small-molecule probes or drugs is a synthetically lengthy, challenging, and resource-intensive process. Lack of automation and reliance on skilled medicinal chemists is cumbersome in both academic and industrial settings. Here, we demonstrate a high-throughput hit-to-lead process based on the biocompatible sulfur­(VI) fluoride exchange (SuFEx) click chemistry. A high-throughput screening hit benzyl (cyanomethyl)­carbamate (K i = 8 μM) against a bacterial cysteine protease SpeB was modified with a SuFExable iminosulfur oxydifluoride [RNS­(O)­F2] motif, rapidly diversified into 460 analogs in overnight reactions, and the products were directly screened to yield drug-like inhibitors with 480-fold higher potency (K i = 18 nM). We showed that the improved molecule is active in a bacteria-host coculture. Since this SuFEx linkage reaction succeeds on picomole scale for direct screening, we anticipate our methodology can accelerate the development of robust biological probes and drug candidates.