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Fragment-based discovery of a small molecule inhibitor of Bruton’s Tyrosine Kinase

Journal Article · · Journal of Medicinal Chemistry
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  1. Takeda California, San Diego, CA (United States)
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The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton’s tyrosine kinase are reported. A fragment-based screening approach incorporating X-ray co-crystallography was used to identify a cinnoline fragment and characterize its binding mode in the ATP binding site of Btk. Optimization of the fragment hit resulted in the identification of a lead compound which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE
OSTI ID:
1213735
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 14 Vol. 58; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (11)

In depth analysis of kinase cross screening data to identify chemical starting points for inhibition of the Nek family of kinases journal January 2018
Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives journal October 2018
Cinnoline Scaffold—A Molecular Heart of Medicinal Chemistry? journal June 2019
Targeting Bruton's tyrosine kinase for the treatment of B cell associated malignancies and autoimmune diseases: Preclinical and clinical developments of small molecule inhibitors journal May 2018
Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations journal May 2018
Water in protein hydration and ligand recognition journal August 2019
Pharmacophore modeling and virtual screening in search of novel Bruton’s tyrosine kinase inhibitors journal June 2019
Unprecedented synthesis of 1,2,3-triazolo-cinnolinone via Sonogashira coupling and intramolecular cyclization journal January 2018
Novel 4-(1H-1,2,3-triazol-4-yl)methoxy)cinnolines as potent antibacterial agents: Synthesis and molecular docking study journal February 2020
Novel 4-(1H-1,2,3-triazol-4-yl)methoxy)cinnolines as potent antibacterial agents: Synthesis and molecular docking study text January 2020
BindingDB Entry 50046163: Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton's Tyrosine Kinase. dataset January 2016

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY