Development of thioquinazolinones, allosteric Chk1 kinase inhibitors.

  title={Development of thioquinazolinones, allosteric Chk1 kinase inhibitors.},
  author={Antonella Converso and Timothy J Hartingh and Robert M. Garbaccio and Edward S Tasber and Keith Rickert and Mark E Fraley and Youwei Yan and Constantine Kreatsoulas and Steve Stirdivant and Bob A Drakas and Eileen S Walsh and Kelly A. Hamilton and Carolyn A. Buser and Xianzhi Mao and Marc T. Abrams and Stephen C. Beck and Weikang Tao and Rob Lobell and Laura Sepp-Lorenzino and Joan Zugay-Murphy and Vinod Sardana and Sanjeev K Munshi and Sylvie Marie Jezequel-Sur and Paul D Zuck and George D. Hartman},
  journal={Bioorganic & medicinal chemistry letters},
  volume={19 4},
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 K(m) 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… CONTINUE READING