Program in Biotechnology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10903, Thailand.
Molecules. 2019 Mar 20;24(6):1092. doi: 10.3390/molecules24061092.
Targeted cancer therapy has become a high potential cancer treatment. Epidermal growth factor receptor (EGFR), which plays an important role in cell signaling, enhanced cell survival and proliferation, has been suggested as molecular target for the development of novel cancer therapeutics. In this study, a series of chalcone derivatives was screened by in vitro cytotoxicity against the wild type (A431 and A549) and mutant EGFR (H1975 and H1650) cancer cell lines, and, subsequently, tested for EGFR-tyrosine kinase (TK) inhibition. From the experimental screening, all chalcones seemed to be more active against the A431 than the A549 cell line, with chalcones , , , , and showing a more than 50% inhibitory activity against the EGFR-TK activity and a high cytotoxicity with IC values of < 10 µM against A431 cells. Moreover, these five chalcones showed more potent on H1975 (T790M/L858R mutation) than H1650 (exon 19 deletion E746-A750) cell lines. Only three chalcones (, and ) had an inhibitory activity against EGFR-TK with a relative inhibition percentage that was close to the approved drug, erlotinib. Molecular dynamics studies on their complexes with EGFR-TK domain in aqueous solution affirmed that they were well-occupied within the ATP binding site and strongly interacted with seven hydrophobic residues, including the important hinge region residue M793. From the above information, as well as ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, all three chalcones could serve as lead compounds for the development of EGFR-TK inhibitors.
靶向癌症疗法已成为一种极具潜力的癌症治疗方法。表皮生长因子受体（EGFR）在细胞信号转导中发挥重要作用，增强细胞存活和增殖，已被认为是开发新型癌症治疗药物的分子靶标。在这项研究中，通过体外细胞毒性筛选了一系列查尔酮衍生物，针对野生型（A431 和 A549）和突变型 EGFR（H1975 和 H1650）癌细胞系，并随后测试了 EGFR-酪氨酸激酶（TK）抑制作用。从实验筛选结果来看，所有查尔酮似乎对 A431 比 A549 细胞系更具活性，查尔酮 、 、 、 、 对 EGFR-TK 活性的抑制活性超过 50%，对 A431 细胞的细胞毒性 IC 值<10µM。此外，这 5 种查尔酮对 H1975（T790M/L858R 突变）的作用比 H1650（外显子 19 缺失 E746-A750）细胞系更有效。只有三种查尔酮（ 、 和 ）对 EGFR-TK 具有抑制活性，相对抑制百分比接近批准药物厄洛替尼。在水溶液中它们与 EGFR-TK 结构域复合物的分子动力学研究证实，它们很好地占据了 ATP 结合位点，并与包括重要铰链区残基 M793 在内的七个疏水性残基强烈相互作用。根据上述信息以及 ADMET（吸收、分布、代谢、排泄和毒性）特性，这三种查尔酮都可以作为开发 EGFR-TK 抑制剂的先导化合物。
