SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase

Zheng, Qinheng; Woehl, Jordan L.; Kitamura, Seiya; Santos-Martins, Diogo; Smedley, Christopher J.; Li, Gencheng; Forli, Stefano; Moses, John E.; Wolan, Dennis W.; Sharpless, K. Barry

doi:10.1073/pnas.1909972116

Cited by 149 publications

(141 citation statements)

References 101 publications

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“…The addition of the phenol ( Figure 6 ) electrophile ( S p- ( 57 )) and ( R p- ( 57 )) conferred a 10-fold increase in potency (Ic 50 of 15 and 17 nM respectively) when compared to parent aptamer ( 63 ) (Ic 50 of 140 nM) in a fluorescence-based hNE inhibition assay. 54 Also small molecules containing the same electrophiles were inactive in this screen (see Supporting Information ). This example further demonstrates the sequence and structure independence of the SENDR platform.…”

Section: Sendr: Complex Settingsmentioning

confidence: 89%

Synthetic Elaboration of Native DNA by RASS (SENDR)

et al. 2020

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Controlled site-specific bioconjugation through chemical methods to native DNA remains an unanswered challenge. Herein, we report a simple solution to achieve this conjugation through the tactical combination of two recently developed technologies: one for the manipulation of DNA in organic media and another for the chemoselective labeling of alcohols. Reversible adsorption of solid support (RASS) is employed to immobilize DNA and facilitate its transfer into dry acetonitrile. Subsequent reaction with P(V)-based Ψ reagents takes place in high yield with exquisite selectivity for the exposed 3′ or 5′ alcohols on DNA. This two-stage process, dubbed SENDR for Synthetic Elaboration of Native DNA by RASS, can be applied to a multitude of DNA conformations and sequences with a variety of functionalized Ψ reagents to generate useful constructs.

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Section: Sendr: Complex Settingsmentioning

confidence: 89%

Synthetic Elaboration of Native DNA by RASS (SENDR)

et al. 2020

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“…It is noteworthy that although analysis of lead‐like structures is a useful exercise, the active compounds from the DOC library each had a large lead‐likeness penalty and, in the majority of cases, are outside of “Lipinski” space (81 %). While the results from the narrow screen do not allow any firm conclusions to be made about specific or special properties of the DOC library per se, they further demonstrate the value of sulfonyl fluoride‐based compounds in lead discovery …”

Section: Resultsmentioning

confidence: 99%

“…Other reactions have since joined the ranks of the click family; each with roots in the “old‐school” literature, including thiol–ene click chemistry—finding wide application in polymer and materials science; Sulfur‐Fluoride Exchange (SuFEx)—a prime method for a wealth of applications, and a powerful diazotransfer agent (diazo‐click) for the guaranteed azidation of primary amines (Figure A) . While these incredibly reliable transformations (Figure ) have become the go‐to click reactions, with few exceptions, the development of the wider family of selective “spring‐loaded” click‐like processes identified in the click chemistry manifesto have been somewhat overlooked (Figure A).…”

Section: Introductionmentioning

confidence: 99%

Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2‐Substituted‐Alkynyl‐1‐Sulfonyl Fluoride (SASF) Hubs

Smedley

Barrow

et al. 2020

Angewandte Chemie

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Diversity Oriented Clicking (DOC) is a unified click‐approach for the modular synthesis of lead‐like structures through application of the wide family of click transformations. DOC evolved from the concept of achieving “diversity with ease”, by combining classic C−C π‐bond click chemistry with recent developments in connective SuFEx‐technologies. We showcase 2‐Substituted‐Alkynyl‐1‐Sulfonyl Fluorides (SASFs) as a new class of connective hub in concert with a diverse selection of click‐cycloaddition processes. Through the selective DOC of SASFs with a range of dipoles and cyclic dienes, we report a diverse click‐library of 173 unique functional molecules in minimal synthetic steps. The SuFExable library comprises 10 discrete heterocyclic core structures derived from 1,3‐ and 1,5‐dipoles; while reaction with cyclic dienes yields several three‐dimensional bicyclic Diels–Alder adducts. Growing the library to 278 discrete compounds through late‐stage modification was made possible through SuFEx click derivatization of the pendant sulfonyl fluoride group in 96 well‐plates—demonstrating the versatility of the DOC approach for the rapid synthesis of diverse functional structures. Screening for function against MRSA (USA300) revealed several lead hits with improved activity over methicillin.

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“…However, several reactive groups have been developed for covalent bond formation at residues other than cysteine (30,32,35). Examples include S(VI)-containing groups sulfonyl fluorides, which react at tyrosine, lysine, or serine residues (30,36,(44)(45)(46)(47). Aryl sulfonyl fluorides provide useful tools to 1) identify amino acids that are amenable to covalent bond formation; 2) uncover new pockets that can be used in drug development; 3) provide starting points to develop derivatives with higher affinity and more suitable reactive groups.…”

Section: Significancementioning

confidence: 99%

Small-molecule covalent bond formation at tyrosine creates a binding site and inhibits activation of Ral GTPases

Bum‐Erdene

Liu

González-Gutiérrez

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Ral (Ras-like) GTPases are directly activated by oncogenic Ras GTPases. Mutant K-Ras (G12C) has enabled the development of covalent K-Ras inhibitors currently in clinical trials. However, Ral, and the overwhelming majority of mutant oncogenic K-Ras, are devoid of a druggable pocket and lack an accessible cysteine for the development of a covalent inhibitor. Here, we report that covalent bond formation by an aryl sulfonyl fluoride electrophile at a tyrosine residue (Tyr-82) inhibits guanine exchange factor Rgl2-mediated nucleotide exchange of Ral GTPase. A high-resolution 1.18-Å X-ray cocrystal structure shows that the compound binds to a well-defined binding site in RalA as a result of a switch II loop conformational change. The structure, along with additional high-resolution crystal structures of several analogs in complex with RalA, confirm the importance of key hydrogen bond anchors between compound sulfone oxygen atoms and Ral backbone nitrogen atoms. Our discovery of a pocket with features found on known druggable sites and covalent modification of a bystander tyrosine residue present in Ral and Ras GTPases provide a strategy that could lead to therapeutic agent targeting oncogenic Ras mutants that are devoid of a cysteine nucleophile.

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SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase

Cited by 149 publications

References 101 publications

Synthetic Elaboration of Native DNA by RASS (SENDR)

Synthetic Elaboration of Native DNA by RASS (SENDR)

Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2‐Substituted‐Alkynyl‐1‐Sulfonyl Fluoride (SASF) Hubs

Small-molecule covalent bond formation at tyrosine creates a binding site and inhibits activation of Ral GTPases

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