College of Pharmacy, Al Ain University, Abu Dhabi 112612, United Arab Emirates.
AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates.
Int J Mol Sci. 2022 Apr 18;23(8):4468. doi: 10.3390/ijms23084468.
Despite available treatments, breast cancer is the leading cause of cancer-related death. Knowing that the tyrosine phosphatase SHP2 is a regulator in tumorigenesis, developing inhibitors of SHP2 in breast cells is crucial. Our study investigated the effects of new compounds, purchased from NSC, on the phosphatase activity of SHP2 and the modulation of breast cancer cell lines' proliferation and viability. A combined ligand-based and structure-based virtual screening protocol was validated, then performed, against SHP2 active site. Top ranked compounds were tested via SHP2 enzymatic assay, followed by measuring IC50 values. Subsequently, hits were tested for their anti-breast cancer viability and proliferative activity. Our experiments identified three compounds , , and as SHP2 inhibitors, with IC50 values in micromolar levels and considerable selectivity over the analogous enzyme SHP1. Long MD simulations of 500 ns showed a very promising binding mode in the SHP2 catalytic pocket. Furthermore, these compounds significantly reduced MCF-7 breast cancer cells' proliferation and viability. Interestingly, two of our hits can have acridine or phenoxazine cyclic system known to intercalate in ds DNA. Therefore, our novel approach led to the discovery of SHP2 inhibitors, which could act as a starting point in the future for clinically useful anticancer agents.
尽管有可用的治疗方法，但乳腺癌仍是癌症相关死亡的主要原因。已知酪氨酸磷酸酶 SHP2 是肿瘤发生的调节剂，因此开发针对乳腺癌细胞的 SHP2 抑制剂至关重要。我们的研究调查了从 NSC 购买的新化合物对 SHP2 磷酸酶活性的影响，以及对乳腺癌细胞系增殖和活力的调节作用。验证了一种基于配体和基于结构的组合虚拟筛选方案，然后针对 SHP2 活性位点进行了筛选。通过 SHP2 酶促测定法测试排名靠前的化合物，然后测量 IC50 值。随后，对这些化合物进行了抗乳腺癌活力和增殖活性测试。我们的实验鉴定出三种化合物 、 和 为 SHP2 抑制剂，IC50 值在微摩尔水平，对类似酶 SHP1 具有相当的选择性。500ns 的长 MD 模拟显示在 SHP2 催化口袋中具有非常有前景的结合模式。此外，这些化合物显著降低了 MCF-7 乳腺癌细胞的增殖和活力。有趣的是，我们的两个命中物都可以具有吖啶或吩嗪的环状系统，已知可以插入 dsDNA。因此，我们的新方法发现了 SHP2 抑制剂，它们可能成为未来临床有用的抗癌药物的起点。
