Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry.

Autor: Guilinger JP; X-Chem Inc., 100 Beaver Street, Waltham, MA 02453, USA. Electronic address: jguilinger@x-chemrx.com., Archna A; Proteros biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany., Augustin M; Proteros biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany., Bergmann A; Proteros biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany., Centrella PA; X-Chem Inc., 100 Beaver Street, Waltham, MA 02453, USA., Clark MA; X-Chem Inc., 100 Beaver Street, Waltham, MA 02453, USA., Cuozzo JW; ZebiAI Inc., 100 Beaver Street, Waltham, MA 02453, USA., Däther M; Proteros biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany., Guié MA; X-Chem Inc., 100 Beaver Street, Waltham, MA 02453, USA., Habeshian S; Laboratory of Therapeutic Proteins and Peptides École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland., Kiefersauer R; Proteros biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany., Krapp S; Proteros biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany., Lammens A; Proteros biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany., Lercher L; Proteros biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany., Liu J; Accent Therapeutics Inc., 65 Hayden Avenue, Lexington, MA 02421, USA., Liu Y; Cyteir Therapeutics, 128 Spring St, Lexington, MA 02421, USA., Maskos K; Proteros biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany., Mrosek M; Bruker AXS GmbH, Karlsruhe, Germany., Pflügler K; Proteros biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany., Siegert M; Proteros biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany., Thomson HA, Tian X; Nurix Therapeutics Inc., 1700 Owens Street, Suite 205 San Francisco, CA 94158, USA., Zhang Y; X-Chem Inc., 100 Beaver Street, Waltham, MA 02453, USA., Konz Makino DL; Proteros biostructures GmbH, Bunsenstr. 7a, 82152 Planegg-Martinsried, Germany. Electronic address: konz-makino@proteros.de., Keefe AD; X-Chem Inc., 100 Beaver Street, Waltham, MA 02453, USA. Electronic address: akeefe@x-chemrx.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2021 Jul 15; Vol. 42, pp. 116223. Date of Electronic Publication: 2021 May 19.
DOI: 10.1016/j.bmc.2021.116223
Abstrakt: Libraries of DNA-Encoded small molecules created using combinatorial chemistry and synthetic oligonucleotides are being applied to drug discovery projects across the pharmaceutical industry. The majority of reported projects describe the discovery of reversible, i.e. non-covalent, target modulators. We synthesized multiple DNA-encoded chemical libraries terminated in electrophiles and then used them to discover covalent irreversible inhibitors and report the successful discovery of acrylamide- and epoxide-terminated Bruton's Tyrosine Kinase (BTK) inhibitors. We also demonstrate their selectivity, potency and covalent cysteine engagement using a range of techniques including X-ray crystallography, thermal transition shift assay, reporter displacement assay and intact protein complex mass spectrometry. The epoxide BTK inhibitors described here are the first ever reported to utilize this electrophile for this target.
(Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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