Download MendeleyDevelopment of thioquinazolinones, allosteric Chk1 kinase inhibitors.
Converso, A., Hartingh, T., Garbaccio, R.M., Tasber, E., Rickert, K., Fraley, M.E., Yan, Y., Kreatsoulas, C., Stirdivant, S., Drakas, B., Walsh, E.S., Hamilton, K., Buser, C.A., Mao, X., Abrams, M.T., Beck, S.C., Tao, W., Lobell, R., Sepp-Lorenzino, L., Zugay-Murphy, J., Sardana, V., Munshi, S.K., Jezequel-Sur, S.M., Zuck, P.D., Hartman, G.D.(2009) Bioorg Med Chem Lett 19: 1240-1244
- PubMed: 19155174
- DOI: https://doi.org/10.1016/j.bmcl.2008.12.076
- Primary Citation of Related Structures:
3F9N - PubMed Abstract:
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 site approximately 13A from the ATP binding site. Preliminary data is presented for several of these compounds.
Organizational Affiliation:
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486, USA. [email protected]
