Abstract

Focal adhesion kinase (FAK) is one kind of tyrosine kinases that modulates integrin and growth factor signaling pathways, which is a promising therapeutic target because of involving in the migration, proliferation and survival of cancer cell. Overexpression and amplification of cyclin-dependent kinase 4/6 (CDK4/6) occur in many cancers and may be the cause of resistance to CDK4/6 inhibitors in preclinical models. The latest research shows that the combination of FAK and CDK4/6 can be dually targeted to enhance the antitumor effects. In this study, FAK and CDK4/6 dual target inhibitors were designed by computer-aided drug design. Seven million molecules were screened by the pharmacophore model and molecular docking. Finally, 6 compounds were obtained. Molecular dynamics simulation of compound 1, 2 and 3 showed that it has good binding stability to both receptors. According to the binding modes of compound 1 with two receptors, corresponding modifications were made, and 7 novel designed compounds were obtained. The docking energy of these novel designed compounds were lower than that of compound 1, and they can be tested in future.

Communicated by Ramaswamy H. Sarma

摘要

粘着斑激酶（FAK）是一种调节整合素和生长因子信号通路的酪氨酸激酶，由于参与癌细胞的迁移、增殖和存活，是一个很有前景的治疗靶点。细胞周期蛋白依赖性激酶 4/6 (CDK4/6) 的过度表达和扩增发生在许多癌症中，并且可能是临床前模型中对 CDK4/6 抑制剂产生耐药性的原因。最新研究表明，FAK和CDK4/6的组合可以双重靶向增强抗肿瘤作用。在本研究中，FAK和CDK4/6双靶点抑制剂采用计算机辅助药物设计。通过药效团模型和分子对接筛选了 700 万个分子。最终得到6个化合物。化合物的分子动力学模拟1，2和3表明它对两种受体都具有良好的结合稳定性。根据化合物1与两种受体的结合方式进行相应修饰，得到7个新设计的化合物。这些新设计的化合物的对接能量低于化合物1，未来可以对其进行测试。

由 Ramaswamy H. Sarma 交流