Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2) is a non-receptor-type protein tyrosine phosphatase (PTP), which is recognized as potential and attractive cancer therapeutic target. Currently, no SHP2 inhibitors have been approved for clinical use, and colorectal cancer (CRC) cells exhibited frequent resistance to reported SHP2 inhibitors, such as SHP099 and TNO155. Herein, we reported our discovery and optimization of phenyl urea as novel SHP2 inhibitors. A8, the most potential SHP2 inhibitor, exhibited great antiproliferative activities against SHP099/TNO155-insensitive tumor cell lines, and rescued PD-L1-mediated immunosuppression. A8 significantly suppressed in vivo tumor growth in a CT26 mouse model and activated immunomodulatory effects in tumor microenvironment. Our work demonstrated that A8 has the potential to be a lead compound for the further development of SHP2 inhibitor and the treatment of CRC.

中文翻译：

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具有抗结肠癌的新型苯基脲 SHP2 抑制剂的发现和潜在的免疫调节作用


含有蛋白酪氨酸磷酸酶-2 （SHP2） 的 Src 同源-2 结构域是一种非受体型蛋白酪氨酸磷酸酶 （PTP），被认为是潜在且有吸引力的癌症治疗靶点。目前，尚无 SHP2 抑制剂被批准用于临床，结直肠癌 （CRC） 细胞对已报道的 SHP2 抑制剂（如 SHP099 和 TNO155）表现出频繁的耐药性。在此，我们报道了苯基脲作为新型 SHP2 抑制剂的发现和优化。A8 是最有潜力的 SHP2 抑制剂，对 SHP099/TNO155 不敏感的肿瘤细胞系表现出强大的抗增殖活性，并挽救了 PD-L1 介导的免疫抑制。A8 在 CT26 小鼠模型中显著抑制体内肿瘤生长，并在肿瘤微环境中激活免疫调节作用。我们的工作表明，A8 有可能成为进一步开发 SHP2 抑制剂和 CRC 治疗的先导化合物。