X-ray structures of checkpoint kinase 2 in complex with inhibitors that target its gatekeeper-dependent hydrophobic pocket |
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Authors: | Lountos George T Jobson Andrew G Tropea Joseph E Self Christopher R Zhang Guangtao Pommier Yves Shoemaker Robert H Waugh David S |
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Institution: | Basic Science Program, SAIC-Frederick, Frederick, MD 21702-1201, USA. |
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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. |
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