以SHP2为靶点已成为一种潜在的癌症治疗策略。本研究首次报道鞣花酸作为SHP2的竞争性抑制剂，IC50值为0.69±0.07μM，其抑制效价是阳性对照NSC87877的34.86倍。鞣花酸对SHP2-E76K和SHP2-E76A突变体也具有较高的抑制活性，IC50值分别为1.55±0.17μM和0.39±0.05μM。此外，鞣花酸对同源蛋白SHP1、PTP1B和TCPTP的IC50值分别为0.93±0.08μM、2.04±0.28μM和11.79±0.83μM，选择性分别为1.35、2.96和17.09倍。 CCK8增殖实验表明，鞣花酸能够抑制多种癌细胞的增殖。值得注意的是，鞣花酸与KRASG12C抑制剂AMG510联合使用，在抑制NCI-H358细胞方面会产生很强的协同作用。 Western blot实验表明，鞣花酸会下调NCI-H358和MDA-MB-468细胞中Erk和Akt的磷酸化水平。分子对接和分子动力学研究揭示了SHP2与鞣花酸之间的结合信息。综上所述，本研究为SHP2抑制剂的开发提供了新思路。版权所有©2023。Elsevier B.V.出版。

Targeting SHP2 has become a potential cancer treatment strategy. In this study, ellagic acid was first reported as a competitive inhibitor of SHP2, with an IC50 value of 0.69 ± 0.07 μM, and its inhibitory potency was 34.86 times higher that of the positive control NSC87877. Ellagic acid also had high inhibitory activity on the SHP2-E76K and SHP2-E76A mutants, with the IC50 values of 1.55 ± 0.17 μM and 0.39 ± 0.05 μM, respectively. Besides, the IC50 values of ellagic acid on homologous proteins SHP1, PTP1B, and TCPTP were 0.93 ± 0.08 μM, 2.04 ± 0.28 μM, and 11.79 ± 0.83 μM, with selectivity of 1.35, 2.96, and 17.09 times, respectively. The CCK8 proliferation experiment exhibited that ellagic acid would inhibit the proliferation of various cancer cells. It was worth noting that the combination of ellagic acid and KRASG12C inhibitor AMG510 would produce a strong synergistic effect in inhibiting NCI-H358 cells. Western blot experiment exhibited that ellagic acid would downregulate the phosphorylation levels of Erk and Akt in NCI-H358 and MDA-MB-468 cells. Molecular docking and molecular dynamics studies revealed the binding information between SHP2 and ellagic acid. In summary, this study provides new ideas for the development of SHP2 inhibitors.Copyright © 2023. Published by Elsevier B.V.