Improved Electrophile Design for Exquisite Covalent Molecule Selectivity

Autor:	José L. Montaño, Brian J. Wang, Regan F. Volk, Sara E. Warrington, Virginia G. Garda, Katherine L. Hofmann, Leo C. Chen, Balyn W. Zaro
Rok vydání:	2022
Předmět:	Proteomics Fumarates Agammaglobulinaemia Tyrosine Kinase Molecular Medicine Cysteine General Medicine Protein Kinase Inhibitors Biochemistry
Zdroj:	ACS Chemical Biology. 17:1440-1449
ISSN:	1554-8937 1554-8929
Popis:	Covalent inhibitors are viable therapeutics. However, off-target reactivity challenges the field. Chemists have attempted to solve this issue by varying the reactivity attributes of electrophilic warheads. Here, we report the development of an approach to increase the selectivity of covalent molecules that is independent of warhead reactivity features and can be used in concert with existing methods. Using the scaffold of the Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib for our proof-of-concept, we reasoned that increasing the steric bulk of fumarate-based electrophiles on Ibrutinib should improve selectivity via the steric exclusion of off-targets but retain rates of cysteine reactivity comparable to that of an acrylamide. Using chemical proteomic techniques, we demonstrate that elaboration of the electrophile to a
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::364ace47f942fd01162d93a41146c42c https://doi.org/10.1021/acschembio.1c00980 Zobrazit plný text záznamu