Development of thioquinazolinones, allosteric Chk1 kinase inhibitors

A high throughput screening campaign was designed to identify allosteric inhibitors of Chk1 kinase by testing compounds at high concentration. Activity was then observed at Km for ATP and at near-physiological concentrations of ATP. This strategy led to the discovery of a non-ATP competitive thioquinazolinone series which was optimized for potency and stability. An X-ray crystal structure for the complex of our best inhibitor bound to Chk1 was solved, indicating that it binds to an allosteric site ∼13 Å from the ATP binding site. Preliminary data is presented for several of these compounds.

Novel thioquinazolinone 38 was identified as allosteric Chk1 kinase inhibitor. An X-ray crystal structure of the first allosteric inhibitor–enzyme complex was solved for this target.Figure optionsDownload as PowerPoint slide