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

ABSTRACT: 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.

SUBMITTER: Alder CM

PROVIDER: S-EPMC4027447 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Alder Catherine M CM Ambler Martin M Campbell Amanda J AJ Champigny Aurelie C AC Deakin Angela M AM Harling John D JD Harris Carol A CA Longstaff Tim T Lynn Sean S Maxwell Aoife C AC Mooney Chris J CJ Scullion Callum C Singh Onkar M P OM Smith Ian E D IE Somers Donald O DO Tame Christopher J CJ Wayne Gareth G Wilson Caroline C Woolven James M JM

ACS medicinal chemistry letters 20130812 10

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 bin ...[more]

PMID: 24900590

Dataset Information

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

Publications

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

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