title: X-ray structures of checkpoint kinase 2 in complex with inhibitors that target its gatekeeper-dependent hydrophobic pocket.
abstract: The serine/threonine checkpoint kinase 2 (Chk2) is an attractive molecular target for the development of small molecule inhibitors to treat cancer. Here, we report the rational design of Chk2 inhibitors that target the gatekeeper-dependent hydrophobic pocket located behind the adenine-binding region of the ATP-binding site. These compounds exhibit IC(50) values in the low nanomolar range and are highly selective for Chk2 over Chk1. X-ray crystallography was used to determine the structures of the inhibitors in complex with the catalytic kinase domain of Chk2 to verify their modes of binding.
authors: Basic Science Program, SAIC-Frederick, Frederick, MD 21702-1201, USA.
authors: George T
authors: GT
authors: Lountos
authors: Andrew G
authors: AG
authors: Jobson
authors: Joseph E
authors: JE
authors: Tropea
authors: Christopher R
authors: CR
authors: Self
authors: Guangtao
authors: G
authors: Zhang
authors: Yves
authors: Y
authors: Pommier
authors: Robert H
authors: RH
authors: Shoemaker
authors: David S
authors: DS
authors: Waugh
mesh_terms: D064447:Checkpoint Kinase 2; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D047428:Protein Kinase Inhibitors; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases