Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK)

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 23; pp. 6331 - 6335
• Main Authors: MacKinnon, Colin H., Lau, Kevin, Burch, Jason D., Chen, Yuan, Dines, Jonathon, Ding, Xiao, Eigenbrot, Charles, Heifetz, Alexander, Jaochico, Allan, Johnson, Adam, Kraemer, Joachim, Kruger, Susanne, Krülle, Thomas M., Liimatta, Marya, Ly, Justin, Maghames, Rosemary, Montalbetti, Christian A.G.N., Ortwine, Daniel F., Pérez-Fuertes, Yolanda, Shia, Steven, Stein, Daniel B., Trani, Giancarlo, Vaidya, Darshan G., Wang, Xiaolu, Bromidge, Steven M., Wu, Lawren C., Pei, Zhonghua
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.12.2013; Elsevier
• Subjects: amides; Animals; Anti-inflammatory; Asthma; Benzothiazole; Benzothiazoles - chemical synthesis; Benzothiazoles - chemistry; Benzothiazoles - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Drug Design; Humans; interleukin-2; ITK inhibitor; Life Sciences & Biomedicine; Mice; Models, Molecular; Pharmacology & Pharmacy; Physical Sciences; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - chemistry; SAR; Science & Technology; Signal Transduction; Structure-Activity Relationship; T-lymphocytes; TCR signalling; tyrosine; X-ray diffraction; ITK inhibitor; TCR signalling; SAR; Anti-inflammatory; Benzothiazole; Asthma; TEC KINASES; TYROSINE KINASE; CRYSTAL-STRUCTURES; DISCOVERY; INSIGHTS; LEAD
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.09.069

Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.