Efficient Ligand Discovery Using Sulfur(VI) Fluoride Reactive Fragments.

Autor:	Aatkar A; GSK, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.; Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K., Vuorinen A; GSK, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.; The Francis Crick Institute, London NW1 1AT, U.K., Longfield OE; GSK, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.; Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K., Gilbert K; GSK, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.; Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K., Peltier-Heap R; GSK, South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Wagner CD; GSK, South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Zappacosta F; GSK, South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Rittinger K; The Francis Crick Institute, London NW1 1AT, U.K., Chung CW; GSK, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., House D; GSK, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.; The Francis Crick Institute, London NW1 1AT, U.K., Tomkinson NCO; Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K., Bush JT; GSK, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.; The Francis Crick Institute, London NW1 1AT, U.K.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2023 Sep 15; Vol. 18 (9), pp. 1926-1937. Date of Electronic Publication: 2023 Apr 21.
DOI:	10.1021/acschembio.3c00034
Abstrakt:	Sulfur(VI) fluorides (SFs) have emerged as valuable electrophiles for the design of "beyond-cysteine" covalent inhibitors and offer potential for expansion of the liganded proteome. Since SFs target a broad range of nucleophilic amino acids, they deliver an approach for the covalent modification of proteins without requirement for a proximal cysteine residue. Further to this, libraries of reactive fragments present an innovative approach for the discovery of ligands and tools for proteins of interest by leveraging a breadth of mass spectrometry analytical approaches. Herein, we report a screening approach that exploits the unique properties of SFs for this purpose. Libraries of SF-containing reactive fragments were synthesized, and a direct-to-biology workflow was taken to efficiently identify hit compounds for CAII and BCL6. The most promising hits were further characterized to establish the site(s) of covalent modification, modification kinetics, and target engagement in cells. Crystallography was used to gain a detailed molecular understanding of how these reactive fragments bind to their target. It is anticipated that this screening protocol can be used for the accelerated discovery of "beyond-cysteine" covalent inhibitors.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu