A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling
A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling
复制标题
DOI：
10.1016/j.cell.2006.03.035
复制
发表时间：
2006-05-19
期刊：
影响因子：
64.5
通讯作者：
Shokat, Kevan M.
中科院分区：
文献类型：
--
作者：
Knight, Zachary A.;Gonzalez, Beatriz;Shokat, Kevan M.
磷脂酰肌醇3-激酶（PI 3-Ks）是一类重要的新兴药物靶点，但PI 3-K亚型的独特作用仍不清楚。我们在这里描述了一种方法来询问PI 3-K家族。合成了一组化学上不同的PI 3-K抑制剂，并对其靶标选择性进行了生化计数，揭示了靶标和化学型之间的神秘同源性。结合到p110 γ的三种抑制剂的晶体结构确定了由选择性化合物唯一利用的构象移动的区域。然后使用该化学阵列来定义胰岛素信号传导所需的PI 3-K亚型。我们发现p110 alpha是培养细胞中主要的胰岛素响应性PI 3-K，而p110 beta是可有可无的，但为p110 alpha活性设定了表型阈值。靶向p110 α的化合物在体内阻断胰岛素治疗的急性效应，而p110 β抑制剂没有作用。这些结果说明了使用跨越蛋白质家族的抑制剂基质的系统靶标验证。
Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110 gamma identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110 alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110 beta is dispensable but sets a phenotypic threshold for p110 alpha activity. Compounds targeting p110 alpha block the acute effects of insulin treatment in vivo, whereas a p110 beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.