Department of Biopharmaceutical Convergence and School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
AbTis Co. Ltd., Suwon 16648, Korea.
Molecules. 2021 Feb 5;26(4):848. doi: 10.3390/molecules26040848.
Natural products have continued to offer tremendous opportunities for drug development, as they have long been used in traditional medicinal systems. SHP2 has served as an anticancer target. To identify novel SHP2 inhibitors with potential anticancer activity, we screened a library containing 658 natural products. Polyphyllin D was found to selectively inhibit SHP2 over SHP1, whereas two other identified compounds (echinocystic acid and oleanolic acid) demonstrated dual SHP1 and SHP2 inhibition. In a cell-based assay, polyphyllin D exhibited cytotoxicity in Jurkat cells, an acute lymphoma leukemia cell line, whereas the other two compounds were ineffective. Polyphyllin D also decreased the level of phosphorylated extracellular signal-regulated kinase (p-ERK), a proliferation marker in Jurkat cells. Furthermore, knockdown of protein tyrosine phosphatase (PTP)N6 (SHP1) or PTPN11 (SHP2) decreased p-ERK levels. However, concurrent knockdown of PTPN6 and PTPN11 in Jurkat cells recovered p-ERK levels. These results demonstrated that polyphyllin D has potential anticancer activity, which can be attributed to its selective inhibition of SHP2 over SHP1.
天然产物一直为药物开发提供了巨大的机会，因为它们长期以来一直被用于传统医学系统。SHP2 一直是抗癌的靶点。为了鉴定具有潜在抗癌活性的新型 SHP2 抑制剂，我们筛选了包含 658 种天然产物的文库。发现重楼苷 D 选择性抑制 SHP2 而不是 SHP1，而另外两种鉴定出的化合物（石榴酸和齐墩果酸）则显示出对 SHP1 和 SHP2 的双重抑制作用。在基于细胞的测定中，重楼苷 D 在 Jurkat 细胞（急性淋巴瘤白血病细胞系）中表现出细胞毒性，而其他两种化合物则无效。重楼苷 D 还降低了 Jurkat 细胞中磷酸化细胞外信号调节激酶（p-ERK）的水平，p-ERK 是增殖标志物。此外，敲低蛋白酪氨酸磷酸酶（PTP）N6（SHP1）或 PTPN11（SHP2）降低了 p-ERK 水平。然而，在 Jurkat 细胞中同时敲低 PTPN6 和 PTPN11 可恢复 p-ERK 水平。这些结果表明，重楼苷 D 具有潜在的抗癌活性，这可归因于其对 SHP2 的选择性抑制作用超过 SHP1。
