Modulating the Binding Kinetics of Bruton’s Tyrosine Kinase Inhibitors through Transition-State Effects
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Le résumé fourni par la source
Optimization exercises strive toward increasing the efficacy and selectivity of small molecules toward the target of interest while simultaneously phasing out design elements that lead to off-target interactions. Given the nonequilibrium nature of biological systems, greater reliance should be placed on engineering kinetic selectivity in addition to equilibrium thermodynamic selectivity; however, the rational design of kinetic selectivity is a challenging endeavor. This study presents a systematic knowledge-based approach to the design of inhibitors that vary in their binding kinetics for Bruton’s tyrosine kinase (BTK), a target for treating B-cell malignancies and autoimmune diseases. A detailed kinetic assessment was performed on existing BTK inhibitors, which, together with structural studies, provided critical insights into BTK-inhibitor interactions that control the kinetics of enzyme inhibition. Subsequently, a series of pyrazolopyrimidines was designed with the objective of modifying interactions between the inhibitor and the regulatory (R) spine in the kinase back pocket, which were hypothesized to modulate the stability of the transition state on the binding reaction coordinate. This resulted in the development of BTK inhibitors with extended residence time in which the variation in k on and k off was uncoupled from equilibrium thermodynamic affinity.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Modulating the Binding Kinetics of Bruton’s Tyrosine Kinase Inhibitors through Transition-State Effects
- Date Crossref
- 29/07/2025
- Éditeur
- American Chemical Society (ACS)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Stony Brook University Department of Applied Mathematics and Statistics pays non établi dans la noticeUniversité ou école supérieure
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Iowa State University pays non établi dans la noticeUniversité ou école supérieure
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Cancer Research UK pays non établi dans la noticeOrganisation à but non lucratif
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University of Rochester pays non établi dans la noticeUniversité ou école supérieure
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Center for the Advanced Study of Drug Action pays non établi dans la noticeInstitution
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Roy J. Carver Department of Biochemistry pays non établi dans la noticeInstitution
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Cancer Research Horizons pays non établi dans la noticeInstitution
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Department of Applied Mathematics and Statistics pays non établi dans la noticeInstitution
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Enzymlogic S.L. pays non établi dans la noticeInstitution
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Laufer Center for Physical and Quantitative Biology pays non établi dans la noticeInstitution
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Department of Biomedical Genetics pays non établi dans la noticeInstitution
Department of Applied Mathematics and Statistics — Stony Brook University, Iowa State University et Cancer Research UK, avec 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.