9EJX

Bruton's tyrosine kinase with mutations in the activation loop in complex with compound PTI42

This is a non-PDB format compatible entry.

Summary for 9EJX

• Entry DOI: 10.2210/pdb9ejx/pdb
• Related: 9EJJ 9EJR 9EJS
• Descriptor: Tyrosine-protein kinase BTK, {(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}(cyclopropyl)methanone (2 entities in total)
• Functional Keywords: inhibitor, kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 1
• Total formula weight: 32276.05

Authors

Lin, D.Y.,Andreotti, A.H.,Tonge, P.J.,Bravo, E.,Li, X. (deposition date: 2024-11-29, release date: 2025-08-13, Last modification date: 2025-08-20)

Primary citation

Bravo Jr., E.,Li, Y.,Lin, D.Y.,Srinivasan, B.,Barone, M.,Li, S.X.,DelloRusso, F.,Rahiyanath, A.S.,Corrionero, A.,Alfonso, P.,Prendiville, N.,Kozakov, D.,Andreotti, A.H.,Tonge, P.J.
Modulating the Binding Kinetics of Bruton's Tyrosine Kinase Inhibitors through Transition-State Effects.
J.Am.Chem.Soc., 147:27876-27891, 2025

PubMed 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 and was uncoupled from equilibrium thermodynamic affinity.

PubMed: 40726426
DOI: 10.1021/jacs.5c07063

Experimental method

X-RAY DIFFRACTION (2.86 Å)