title: Structural characterization of inhibitor complexes with checkpoint kinase 2 (Chk2), a drug target for cancer therapy.
abstract: Chk2 (checkpoint kinase 2) is a serine/threonine kinase that participates in a series of signaling networks responsible for maintaining genomic integrity and responding to DNA damage. The development of selective Chk2 inhibitors has recently attracted much interest as a means of sensitizing cancer cells to current DNA-damaging agents used in the treatment of cancer. Additionally, selective Chk2 inhibitors may reduce p53-mediated apoptosis in normal tissues, thereby helping to mitigate adverse side effects from chemotherapy and radiation. Thus far, relatively few selective inhibitors of Chk2 have been described and none have yet progressed into clinical trials. Here, we report crystal structures of the catalytic domain of Chk2 in complex with a novel series of potent and selective small molecule inhibitors. These compounds exhibit nanomolar potencies and are selective for Chk2 over Chk1. The structures reported here elucidate the binding modes of these inhibitors to Chk2 and provide information that can be exploited for the structure-assisted design of novel chemotherapeutics.
authors.affiliation: Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702-1201, USA.
authors.forename: George T
authors.initials: GT
authors.lastname: Lountos
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Jobson
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Tropea
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Self
authors.forename: Guangtao
authors.initials: G
authors.lastname: Zhang
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Robert H
authors.initials: RH
authors.lastname: Shoemaker
authors.forename: David S
authors.initials: DS
authors.lastname: Waugh
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D018360:Crystallography, X-Ray; D006801:Humans; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011494:Protein Kinases / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases