X 射线结构的检查点激酶 2 与抑制剂的复合物，该抑制剂针对其依赖于守门员的疏水性口袋。
X-ray structures of checkpoint kinase 2 in complex with inhibitors that target its gatekeeper-dependent hydrophobic pocket.
机构信息
Basic Science Program, SAIC-Frederick, Frederick, MD 21702-1201, USA.
出版信息
FEBS Lett. 2011 Oct 20;585(20):3245-9. doi: 10.1016/j.febslet.2011.08.050. Epub 2011 Sep 7.
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.
摘要
丝氨酸/苏氨酸检查点激酶 2（Chk2）是开发小分子抑制剂治疗癌症的有吸引力的分子靶标。在这里，我们报告了针对位于 ATP 结合位点的腺嘌呤结合区域后面的依赖于门控的疏水性口袋的 Chk2 抑制剂的合理设计。这些化合物在低纳摩尔范围内表现出 IC（50）值，并且对 Chk2 相对于 Chk1 具有高度选择性。X 射线晶体学被用于确定抑制剂与 Chk2 的催化激酶结构域的复合物结构，以验证它们的结合模式。
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