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Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy

2013; American Chemical Society; Volume: 4; Issue: 10 Linguagem: Inglês

10.1021/ml400206q

1948-5875

Catherine M. Alder, Martin Ambler, Amanda Campbell, Aurélie C. Champigny, Angela M. Deakin, John D. Harling, Carol Harris, Tim Longstaff, Sean M. Lynn, Aoife C. Maxwell, Chris J. Mooney, Callum Scullion, Onkar Singh, Ian E. Smith, D.O. Somers, Christopher J. Tame, Gareth Wayne, Caroline Wilson, James M. Woolven,

Microtubule and mitosis dynamics

Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays.