Discovery of novel phenyl urea SHP2 inhibitors with anti-colon cancer and potential immunomodulatory effects

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-11-06 DOI:10.1016/j.ejmech.2024.117036

Kaizhen Wang , Xiangyu Zhang , Yingxin Hu, Jiazheng Guo, Guoqing Shen, Kuojun Zhang, Sheng Jiang, Tianyu Wang

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Abstract

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.

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发现具有抗结肠癌和潜在免疫调节作用的新型苯基尿素 SHP2 抑制剂

Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2（SHP2）是一种非受体型蛋白酪氨酸磷酸酶（PTP），被认为是潜在的、有吸引力的癌症治疗靶点。目前，还没有SHP2抑制剂被批准用于临床，而且结直肠癌（CRC）细胞对已报道的SHP2抑制剂（如SHP099和TNO155）经常表现出耐药性。在此，我们报告了苯脲作为新型 SHP2 抑制剂的发现和优化。A8是最有潜力的SHP2抑制剂，它对SHP099/TNO155不敏感的肿瘤细胞株具有很强的抗增殖活性，并能挽救PD-L1介导的免疫抑制。在 CT26 小鼠模型中，A8 能明显抑制体内肿瘤生长，并激活肿瘤微环境中的免疫调节作用。我们的研究表明，A8 有潜力成为进一步开发 SHP2 抑制剂和治疗 CRC 的先导化合物。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.