Structural basis for Chk1 inhibition by UCN-01

J Biol Chem. 2002 Nov 29;277(48):46609-15. doi: 10.1074/jbc.M201233200. Epub 2002 Sep 19.

Abstract

Chk1 is a serine-threonine kinase that plays an important role in the DNA damage response, including G(2)/M cell cycle control. UCN-01 (7-hydroxystaurosporine), currently in clinical trials, has recently been shown to be a potent Chk1 inhibitor that abrogates the G(2)/M checkpoint induced by DNA-damaging agents. To understand the structural basis of Chk1 inhibition by UCN-01, we determined the crystal structure of the Chk1 kinase domain in complex with UCN-01. Chk1 structures with staurosporine and its analog SB-218078 were also determined. All three compounds bind in the ATP-binding pocket of Chk1, producing only slight changes in the protein conformation. Selectivity of UCN-01 toward Chk1 over cyclin-dependent kinases can be explained by the presence of a hydroxyl group in the lactam moiety interacting with the ATP-binding pocket. Hydrophobic interactions and hydrogen-bonding interactions were observed in the structures between UCN-01 and the Chk1 kinase domain. The high structural complementarity of these interactions is consistent with the potency and selectivity of UCN-01.

MeSH terms

  • Alkaloids / chemistry
  • Alkaloids / pharmacology*
  • Amino Acid Sequence
  • Checkpoint Kinase 1
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Protein Kinase Inhibitors*
  • Protein Kinases / chemistry
  • Staurosporine / analogs & derivatives
  • Structure-Activity Relationship

Substances

  • Alkaloids
  • Protein Kinase Inhibitors
  • 7-hydroxystaurosporine
  • Protein Kinases
  • Checkpoint Kinase 1
  • Staurosporine