Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK).
MacKinnon CH, Lau K, Burch JD, Chen Y, Dines J, Ding X, Eigenbrot C, Heifetz A, Jaochico A, Johnson A, Kraemer J, Kruger S, Krülle TM, Liimatta M, Ly J, Maghames R, Montalbetti CA, Ortwine DF, Pérez-Fuertes Y, Shia S, Stein DB, Trani G, Vaidya DG, Wang X, Bromidge SM, Wu LC, Pei Z.
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.