公开(公告)号：US20100168162A1

公开(公告)日：2010-07-01

申请号：US12645313

申请日：2009-12-22

申请人： Ze'ev Ronai ,  Maurizio Pellecchia ,  Gary Chiang

发明人： Ze'ev Ronai ,  Maurizio Pellecchia ,  Gary Chiang

IPC分类号： A61K31/4709 ,  C07D401/06 ,  A61P35/00

CPC分类号： A61K31/415 ,  A61K31/47 ,  C07D215/227 ,  C07D307/46 ,  C07D401/06 ,  C07D405/06 ,  C07D471/04

摘要： The present invention describes an improved method for screening compounds for activity in inhibiting the enzymatic activity of Akt1 protein kinase, also known as Protein Kinase B, an enzyme that is believed to play a key role in the inhibition of apoptosis and thus in the etiology of cancer and other conditions, including neurodegenerative diseases. In general, the method comprises: (1) providing a plurality of compounds suspected of having Akt1 kinase inhibitory activity; (2) modeling the docking of each of the plurality of the compounds with a target binding site derived from the crystal structure of a ternary complex involving Akt1, a nonhydrolyzable ATP analogue, and a peptide substrate derived from a physiological AKT substrate such that the protein active site is defined including those residues within a defined distance from the nonhydrolyzable ATP analogue; (3) ranking the docked compounds by goodness of fit; (4) further selecting compounds from compounds high ranked by goodness of fit in docking by using one or more screening criteria; (5) optionally, visually analyzing structures of compounds selected in step (4) to remove any compounds with improbable docking geometry; and (6) experimentally testing the selected compounds from step (4) or step (5), if step (5) is performed, to determine their inhibitory activity against Akt1 in order to select compounds with Akt1 inhibitory activity. The invention also encompasses pharmaceutical compositions including compounds whose inhibitory activity against Akt1 is discovered by the screening method, as well as methods of use of the pharmaceutical compositions to treat cancer and other conditions.

摘要翻译： 本发明描述了一种用于筛选化合物以抑制Akt1蛋白激酶（也称为蛋白激酶B）的酶活性的活性的改进方法，该酶被认为在抑制细胞凋亡中起着关键作用，因此在病因 癌症等病症，包括神经退行性疾病。 通常，该方法包括：（1）提供疑似具有Akt1激酶抑制活性的多种化合物; （2）将来自多个化合物中的每一个的引物与衍生自涉及Akt1，不可水解的ATP类似物的三元复合物的晶体结构的靶结合位点和衍生自生理学AKT底物的肽底物进行建模，使得蛋白质 定义活性位点，包括距离不可水解的ATP类似物限定距离内的那些残基; （3）通过拟合优点对准对接化合物; （4）通过使用一种或多种筛选标准，进一步选择化合物，所述化合物是通过拟合优先顺序进行对接的化合物; （5）任选地，目视分析在步骤（4）中选择的化合物的结构以除去具有不可能的对接几何形状的任何化合物; （6）如果进行步骤（5），则从步骤（4）或步骤（5）中选出的化合物进行实验测试，以确定其对Akt1的抑制活性，以选择具有Akt1抑制活性的化合物。 本发明还包括药物组合物，其包括通过筛选方法发现对Akt1的抑制活性的化合物，以及药物组合物用于治疗癌症和其它病症的方法。

公开(公告)号：US20120190707A1

公开(公告)日：2012-07-26

申请号：US13357541

申请日：2012-01-24

申请人： Ze'ev Ronai ,  Maurizio Pellecchia ,  Gary Chiang

发明人： Ze'ev Ronai ,  Maurizio Pellecchia ,  Gary Chiang

IPC分类号： A61K31/4709 ,  C07D471/04 ,  C07D401/10 ,  A61K31/4704 ,  A61P35/00 ,  A61P25/28 ,  C07D401/06 ,  C07D215/227

CPC分类号： A61K31/415 ,  A61K31/47 ,  C07D215/227 ,  C07D307/46 ,  C07D401/06 ,  C07D405/06

摘要： The present invention describes an improved method for screening compounds for activity in inhibiting the enzymatic activity of Akt1 protein kinase. In general, the method comprises: (1) providing a plurality of compounds suspected of having Akt1 kinase inhibitory activity; (2) modeling the docking of each of the plurality of the compounds with a target binding site; (3) ranking the docked compounds by goodness of fit; (4) further selecting compounds; (5) optionally, visually analyzing structures of compounds selected in step (4) to remove any compounds with improbable docking geometry; and (6) experimentally testing the selected compounds from step (4) or step (5), if step (5) is performed, to determine their inhibitory activity against Akt1. The invention also encompasses pharmaceutical compositions including compounds whose inhibitory activity against Akt1 is discovered by the screening method, as well as methods of use of the pharmaceutical compositions to prevent and treat cancer and other conditions.

摘要翻译： 本发明描述了一种用于筛选化合物以抑制Akt1蛋白激酶的酶活性的活性的改进方法。 通常，该方法包括：（1）提供疑似具有Akt1激酶抑制活性的多种化合物; （2）建模多个化合物中的每一个与靶结合位点的对接; （3）通过拟合优点对准对接化合物; （4）进一步选择化合物; （5）任选地，目视分析在步骤（4）中选择的化合物的结构以除去具有不可能的对接几何形状的任何化合物; 和（6）如果进行步骤（5），则从步骤（4）或步骤（5）中实验测试所选择的化合物，以确定其对Akt1的抑制活性。 本发明还包括药物组合物，包括通过筛选方法发现对Akt1的抑制活性的化合物，以及药物组合物用于预防和治疗癌症和其它病症的方法。