Kim Min Kyoung, Min Jaeki, Choi Bu-Young, Lim Haeyoung, Cho Youl-Hee, Lee Chul-Hoon
Department of Medical Genetics, College of Medicine, Hanyang University, Seoul, Korea.
J Microbiol Biotechnol. 2007 Oct;17(10):1712-6.
To generate new scaffold candidates as highly selective and potent cyclin-dependent kinase (CDK) inhibitors, structure-based drug screening was performed utilizing 3D pharmacophore conformations of known potent inhibitors. As a result, CR229 (6-bromo-2,3,4,9-tetrahydro-carbolin-1-one) was generated as the hit-compound. A computational docking study using the X-ray crystallographic structure of CDK2 in complex with CR229 was evaluated. This predicted binding mode study of CR229 with CDK2 demonstrated that CR229 interacted effectively with the Leu83 and Glu81 residues in the ATP-binding pocket of CDK2 for the possible hydrogen bond formation. Furthermore, biochemical studies on inhibitory effects of CR229 on various kinases in the human cervical cancer HeLa cells demonstrated that CR229 was a potent inhibitor of CDK2 (IC50: 3 microM), CDK1 (IC50: 4.9 microM), and CDK4 (IC50: 3 microM), yet had much less inhibitory effect (IC50: >20 microM) on other kinases, such as casein kinase 2-1 (CK2- alpha1), protein kinase A (PKA), and protein kinase C (PKC). Accordingly, these data demonstrate that CR229 is a potent CDK inhibitor with anticancer efficacy.
为了生成作为高选择性和强效细胞周期蛋白依赖性激酶（CDK）抑制剂的新支架候选物，利用已知强效抑制剂的3D药效团构象进行了基于结构的药物筛选。结果，生成了命中化合物CR229（6-溴-2,3,4,9-四氢咔啉-1-酮）。评估了使用与CR229复合的CDK2的X射线晶体结构进行的计算对接研究。CR229与CDK2的这种预测结合模式研究表明，CR229与CDK2的ATP结合口袋中的Leu83和Glu81残基有效相互作用，可能形成氢键。此外，关于CR229对人宫颈癌HeLa细胞中各种激酶抑制作用的生化研究表明，CR229是CDK2（IC50：3 microM）、CDK1（IC50：4.9 microM）和CDK4（IC50：3 microM）的强效抑制剂，但对其他激酶，如酪蛋白激酶2-1（CK2-α1）、蛋白激酶A（PKA）和蛋白激酶C（PKC）的抑制作用要小得多（IC50：>20 microM）。因此，这些数据表明CR229是一种具有抗癌功效的强效CDK抑制剂。
