Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors

作者：Pastor Richard M^*; Burch Jason D; Magnuson Steven; Ortwine Daniel F; Chen Yuan; De La Torre Kelly; Ding Xiao; Eigenbrot Charles; Johnson Adam; Liimatta Marya; Liu Yichin; Shia Steven; Wang Xiaolu; Wu Lawren C; Pei Zhonghua

来源：Bioorganic & Medicinal Chemistry Letters, 2014, 24(11): 2448-2452.

DOI：10.1016/j.bmcl.2014.04.023

• SBDD
• ITK
• Indazole
• X-ray crystallography
• pi-stacking

There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes.

• 出版日期2014-6-1