Design and Synthesis of Small Molecule RhoA Inhibitors: A New Promising Therapy for Cardiovascular Diseases?
Design and Synthesis of Small Molecule RhoA Inhibitors: A New Promising Therapy for Cardiovascular Diseases?
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小分子 RhoA 抑制剂的设计与合成：心血管疾病的新疗法？
DOI：
10.1021/jm200161c
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发表时间：
2011-07-14
影响因子：
7.3
通讯作者：
Li, Jian
中科院分区：
文献类型：
--
作者：
Deng, Jing;Feng, Enguang;Li, Jian
RhoA是Rho GTPases的成员，Rho GTPases是小GTP结合蛋白Ras超家族的亚组。RhoA作为多种细胞信号通路的重要调节因子，在细胞骨架的构建、转录和细胞周期进程中发挥重要作用。RhoA/ROCK抑制剂已成为心血管疾病的一种新的有前途的治疗方法。然而，迄今为止，RhoA抑制剂是大分子，并且据我们所知，基于小分子的抑制剂尚未报道。在这项研究中，一系列一流的小分子RhoA抑制剂已被发现，通过使用基于结构的虚拟筛选结合化学合成和生物测定。对类似于200，000种化合物进行虚拟筛选，然后进行基于SPR的结合亲和力测定，得到三种化合物，其对RhoA具有微摩尔水平的结合亲和力（化合物1-3）。考虑到结合活性和合成容易性，选择化合物1用于进一步的结构修饰。据此设计并合成了41个新化合物（1、12 a-v、13 a-h和14 a-j）。结果表明，8个化合物（12 a，12 j，14 a，14 b，14 d，14 e，14 g，14 h）具有较高的RhoA抑制活性，IC（50）值为1.24 ~ 3.00 μ M。药理学试验表明，两个化合物（14 g和14 h）对PE诱导的胸主动脉环收缩表现出明显的血管舒张作用，并为开发更有效的心血管药物提供了良好的线索。
RhoA is a member of Rho GTPases, a subgroup of the Ras superfamily of small GTP-binding proteins. RhoA, as important regulator of diverse cellular signaling pathways, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. The RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. However, to date, RhoA inhibitors are macromolecules, and to our knowledge, small molecular-based inhibitors have not been reported. In this study, a series of first-in-class small molecular RhoA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. Virtual screening of similar to 200,000 compounds, followed by SPR-based binding affinity assays resulted in three compounds with binding affinities to RhoA at the micromolar level (compounds 1-3). Compound 1 was selected for further structure modifications in considering binding activity and synthesis ease. Fourty-one new compounds (1, 12a-v, 13a-h, and 14a-j) were designed and synthesized accordingly. It was found that eight (12a, 12j, 14a, 14b, 14d, 14e, 14 g, and 14h) showed high RhoA inhibition activities with IC(50) values of 1.24 to 3.00 mu M. A pharmacological assay indicated that two compounds (14g and 14 h) demonstrated noticeable vasorelaxation effects against PE-induced contraction in thoracic aorta artery rings and served as good leads for developing more potent cardiovascular agents.