2. Academic Validation
  3. Modulating the Binding Kinetics of Bruton's Tyrosine Kinase Inhibitors through Transition-State Effects

Modulating the Binding Kinetics of Bruton's Tyrosine Kinase Inhibitors through Transition-State Effects

  • J Am Chem Soc. 2025 Aug 6;147(31):27876-27891. doi: 10.1021/jacs.5c07063.
Eduardo Bravo Jr 1,  Yong Li 1,  David Yin-Wei Lin 2,  Bharath Srinivasan 1 3,  Marco Barone 1,  Stan Xiaogang Li 1 4,  Francesca DelloRusso 1,  Anza Suneer Rahiyanath 1,  Ana Corrionero 5,  Patricia Alfonso 5,  Niall Prendiville 5,  Dima Kozakov 6 4,  Amy H Andreotti 2,  Peter J Tonge 1 6 7
Affiliations

Affiliations

  • 1 Center for the Advanced Study of Drug Action, Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400, United States.
  • 2 Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa 50011, United States.
  • 3 Cancer Research Horizons, Cancer Research U.K., Cambridge CB2 0RE, U.K.
  • 4 Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York 11794-3400, United States.
  • 5 Enzymlogic S.L., QUBE Technology Park, C/Santiago Grisolía, 2, 28760 Madrid, Spain.
  • 6 Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York 11794-3400, United States.
  • 7 Department of Biomedical Genetics, University of Rochester, Rochester, New York 14642, United States.
PMID: 40726426 DOI: 10.1021/jacs.5c07063
Abstract

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 kon and koff was uncoupled from equilibrium thermodynamic affinity.

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