Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK)

Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK)

Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-base...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2014-12, Vol.24 (24), p.5818-5823
Hauptverfasser: Trani, Giancarlo, Barker, John J, Bromidge, Steven M, Brookfield, Frederick A, Burch, Jason D, Chen, Yuan, Eigenbrot, Charles, Heifetz, Alexander, Ismaili, M Hicham A, Johnson, Adam, Krülle, Thomas M, MacKinnon, Colin H, Maghames, Rosemary, McEwan, Paul A, Montalbetti, Christian A G N, Ortwine, Daniel F, Pérez-Fuertes, Yolanda, Vaidya, Darshan G, Wang, Xiaolu, Zarrin, Ali A, Pei, Zhonghua
Format: Artikel
Sprache:eng
Schlagworte:
Binding Sites
Crystallography, X-Ray
Drug Design
Kinetics
Molecular Dynamics Simulation
Protein Binding
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - metabolism
Protein Structure, Tertiary
Protein-Tyrosine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - metabolism
Pyrazoles - chemistry
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - metabolism
Structure-Activity Relationship
Sulfones - chemistry
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Beschreibung
Zusammenfassung:Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2014.10.020