AI Article Synopsis
- Inhibition of Itk could be a new nonsteroidal treatment option for asthma and other diseases related to T-cells.
- In-house screening found a series of Itk inhibitors based on aminopyrazole, but initially faced selectivity problems with other kinases like AurA and AurB.
- A new approach using a different chemical structure (aminobenzothiazole) improved selectivity, and studies using crystallography and modeling helped understand this selectivity while identifying effective Itk inhibitors.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027447 | PMC |
| http://dx.doi.org/10.1021/ml400206q | DOI Listing |
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