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Design, synthesis, and biological evaluation of novel substituted thiourea derivatives as potential anticancer agents for NSCLC by blocking K-Ras protein-effectors interactions.
Journal of Enzyme inhibition and Medicinal Chemistry ( IF 5.6 ) Pub Date : 2019-12-18 , DOI: 10.1080/14756366.2019.1702653
Yuan Zhang 1 , Xin Meng 1 , Haikang Tang 1 , Minghui Cheng 1 , Fujun Yang 1 , Wenqing Xu 1
Affiliation  

Mutation of the proto-oncogene K-Ras is one of the most common molecular mechanisms in non-small cell lung cancer. Many drugs for treating lung cancer have been developed, however, due to clinical observed K-Ras mutations, corresponding chemotherapy and targeted therapy for such mutation are not efficient enough. In this study, on the basis of the crystal structure of K-Ras, 21 analogues (TKR01-TKR21) containing urea or thiourea were rationally designed, which can effectively inhibit the lung cancer cell A549 growth. The designing of these compounds was based on the structure of K-Ras protein, and the related groups were replaced by bioisosteres to improve the affinity and selectivity. Biological testing revealed that compound TKR15 could significantly inhibit the proliferation of A549 cell with IC50 of 0.21 µM. Docking analysis showed that the TKR15 can effectively bind to the hydrophobic cavity and form a hydrogen bond with the Glu37. In addition, through flow apoptosis assay and immunofluorescence staining assay, it confirmed that this compound can inhibit A549 cell proliferation with the mechanism of blocking K-RasG12V protein and effector proteins interactions through the apoptotic pathway. In conclusion, our studies in finding novel potent compound (TKR15) with confirmed mechanism showed great potential for further optimisation and other medicinal chemistry relevant studies.

中文翻译:

通过阻断K-Ras蛋白效应子的相互作用,设计,合成和生物学评估新型取代的硫脲衍生物作为NSCLC的潜在抗癌剂。

原癌基因K-Ras的突变是非小细胞肺癌中最常见的分子机制之一。已经开发了许多用于治疗肺癌的药物,但是,由于临床观察到的K-Ras突变,相应的化学疗法和针对这种突变的靶向治疗不够有效。在这项研究中,基于K-Ras的晶体结构,合理设计了21种含有尿素或硫脲的类似物(TKR01-TKR21),可以有效抑制肺癌细胞A549的生长。这些化合物的设计基于K-Ras蛋白的结构,相关基团被生物等排物取代,以提高亲和力和选择性。生物测试表明,化合物TKR15可以显着抑制A549细胞的增殖,IC50为0.21 µM。对接分析表明,TKR15可以有效结合疏水腔,并与Glu37形成氢键。另外,通过流式细胞术和免疫荧光染色法证实,该化合物具有抑制A549细胞增殖的作用,其机制是通过凋亡途径阻断K-RasG12V蛋白和效应蛋白的相互作用。总之,我们在寻找具有确定机理的新型强效化合物(TKR15)方面的研究显示出了进一步优化和其他药物化学相关研究的巨大潜力。它证实了该化合物可以通过阻断K-RasG12V蛋白和效应蛋白通过凋亡途径的相互作用来抑制A549细胞的增殖。总而言之,我们在寻找具有确定机理的新型有效化合物(TKR15)方面的研究显示出了进一步优化和其他药物化学相关研究的巨大潜力。它证实了该化合物可以通过阻断K-RasG12V蛋白和效应蛋白通过凋亡途径的相互作用来抑制A549细胞的增殖。总而言之,我们在寻找具有确定机理的新型有效化合物(TKR15)方面的研究显示出了进一步优化和其他药物化学相关研究的巨大潜力。
更新日期:2020-04-20
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