用于 SHP2 蛋白降解的新型 PROTACs。
Novel PROTACs for degradation of SHP2 protein.
机构信息
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
出版信息
Bioorg Chem. 2021 May;110:104788. doi: 10.1016/j.bioorg.2021.104788. Epub 2021 Mar 1.
Protein tyrosine phosphatase SHP2 is a member of PTPs family associated with cancer such as leukemia, non-small cell lung cancer, breast cancer, and so on. SHP2 is a promising target for drug development, and consequently it is of great significance to develop SHP2 inhibitors. Herein, we report CRBN-recruiting PROTAC molecules targeting SHP2 by connecting pomalidomide with SHP099, an allosteric inhibitor of SHP2. Among them, SP4 significantly inhibited the growth of Hela cells, compared with SHP099, its activity increased 100 times. In addition, it can significantly induce SHP2 degradation and cell apoptosis. Further study of SHP2-protac may have important significance for the treatment of SHP2 related diseases.
蛋白酪氨酸磷酸酶 SHP2 是与癌症（如白血病、非小细胞肺癌、乳腺癌等）相关的 PTPs 家族的一员。SHP2 是药物开发的一个有前途的靶点，因此开发 SHP2 抑制剂具有重要意义。在这里，我们报告了通过将泊马度胺与 SHP099（SHP2 的别构抑制剂）连接，开发出针对 SHP2 的 CRBN 募集 PROTAC 分子。其中，SP4 显著抑制了 Hela 细胞的生长，与 SHP099 相比，其活性增加了 100 倍。此外，它还能显著诱导 SHP2 降解和细胞凋亡。进一步研究 SHP2-protac 可能对治疗 SHP2 相关疾病具有重要意义。
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