The SH3 domain of Bruton's tyrosine kinase displays altered ligand binding properties when auto‐phosphorylated<i>in vitro</i>

Morrogh, Lucy MacCarthy; Hinshelwood, Steve; Costello, Patrick; Cory, Giles O.; Kinnon, Christine

doi:10.1002/(sici)1521-4141(199907)29:07<2269::aid-immu2269>3.0.co;2-#

Cited by 50 publications

References 35 publications

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Interaction between Btk TH and SH3 domain

Okoh

Vihinen

2002

Biopolymers

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Several mechanisms are involved in the regulation of cellular signaling. Bruton tyrosine kinase (Btk) of the Tec family contains in the Tec homology (TH) domain a proline-rich region (PRR) capable of interacting with several SH3 domains. The Btk has the SH3 domain adjacent to the TH domain. CD and fluorescence spectroscopy were used to study the binding of two peptides corresponding to segments in the PRR to the Btk SH3 domain. The peptide for the N-terminal half of the PRR binds specifically, whereas the other peptide had hardly any affinity. The TH domain has about four times lower affinity to the SH3 domain than the peptide, 17.0 vs 3.9 microM. The interaction was further tested with an SH3 domain construct that contained the PRR. The two peptides cannot compete for the binding to the extended protein and the TH domain has two times lower affinity to the extended SH3 domain. The intra- or intermolecular interaction between the TH and SH3 domain might have regulatory function also in the other Tec family members.

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Interaction between Btk TH and SH3 domain

Okoh

Vihinen

2002

Biopolymers

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Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC‐0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor

Herman¹,

Chinn²,

Kotwal³

et al. 2018

Clin Pharma and Therapeutics

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GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well tolerated, with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose (SAD) study; ≤250 mg twice daily (b.i.d.) and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study). Plasma concentrations peaked 1-3 hours after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 hours. Independent assays demonstrated dose-dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once-daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC-0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications.

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Competitive Binding of Proline-Rich Sequences by SH3, WW, and Other Functionally Related Protein Domains

Sudol

Bedford

2005

Proteomics and Protein-Protein Interactions

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The SH3 domain of Bruton's tyrosine kinase displays altered ligand binding properties when auto‐phosphorylatedin vitro

Cited by 50 publications

References 35 publications

Interaction between Btk TH and SH3 domain

Interaction between Btk TH and SH3 domain

Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC‐0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor

Competitive Binding of Proline-Rich Sequences by SH3, WW, and Other Functionally Related Protein Domains

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