Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry.
Bruton’s Tyrosine Kinase
Covalent Irreversible Inhibitor
DNA-Encoded Chemical Libraries (DECL)
Drug Discovery
Epoxide
Tryptoline
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
15 07 2021
15 07 2021
Historique:
received:
28
02
2021
revised:
11
05
2021
accepted:
13
05
2021
pubmed:
7
6
2021
medline:
16
12
2021
entrez:
6
6
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34091303
pii: S0968-0896(21)00231-5
doi: 10.1016/j.bmc.2021.116223
pii:
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Small Molecule Libraries
0
DNA
9007-49-2
Agammaglobulinaemia Tyrosine Kinase
EC 2.7.10.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
116223Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.