鉴定乙烯砜衍生物为 EGFR 酪氨酸激酶抑制剂：体外和计算研究。

Identification of Vinyl Sulfone Derivatives as EGFR Tyrosine Kinase Inhibitor: In Vitro and In Silico Studies.

机构信息

Biocatalyst and Environmental Biotechnology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.

Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.

出版信息

Molecules. 2021 Apr 12;26(8):2211. doi: 10.3390/molecules26082211.

Epidermal growth factor receptor (EGFR), overexpressed in many types of cancer, has been proved as a high potential target for targeted cancer therapy due to its role in regulating proliferation and survival of cancer cells. In the present study, a series of designed vinyl sulfone derivatives was screened against EGFR tyrosine kinase (EGFR-TK) using in silico and in vitro studies. The molecular docking results suggested that, among 78 vinyl sulfones, there were eight compounds that could interact well with the EGFR-TK at the ATP-binding site. Afterwards, these screened compounds were tested for the inhibitory activity towards EGFR-TK using ADP-Glo™ kinase assay, and we found that only VF16 compound exhibited promising inhibitory activity against EGFR-TK with the IC value of 7.85 ± 0.88 nM. In addition, VF16 showed a high cytotoxicity with IC values of 33.52 ± 2.57, 54.63 ± 0.09, and 30.38 ± 1.37 µM against the A431, A549, and H1975 cancer cell lines, respectively. From 500-ns MD simulation, the structural stability of VF16 in complex with EGFR-TK was quite stable, suggesting that this compound could be a novel small molecule inhibitor targeting EGFR-TK.

表皮生长因子受体（EGFR）在许多类型的癌症中过度表达，由于其在调节癌细胞增殖和存活中的作用，已被证明是靶向癌症治疗的一个有很大潜力的靶点。在本研究中，通过计算机筛选和体外研究，对一系列设计的乙烯砜衍生物进行了针对 EGFR 酪氨酸激酶（EGFR-TK）的筛选。分子对接结果表明，在 78 个乙烯砜中，有 8 个化合物可以与 EGFR-TK 在 ATP 结合位点很好地相互作用。随后，使用 ADP-Glo™激酶测定法测试了这些筛选出的化合物对 EGFR-TK 的抑制活性，我们发现只有 VF16 化合物对 EGFR-TK 表现出有希望的抑制活性，IC 值为 7.85±0.88 nM。此外，VF16 对 A431、A549 和 H1975 癌细胞系的 IC 值分别为 33.52±2.57、54.63±0.09 和 30.38±1.37µM，表现出高细胞毒性。从 500-ns MD 模拟来看，VF16 与 EGFR-TK 复合物的结构稳定性相当稳定，表明该化合物可能是一种针对 EGFR-TK 的新型小分子抑制剂。