Department of Medicine, Division of Hematology and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, Ohio 44106, United States.
J Med Chem. 2013 Sep 26;56(18):7212-21. doi: 10.1021/jm400474r. Epub 2013 Sep 4.
Activating mutations of PTPN11 (encoding the SHP2 phosphatase) are associated with Noonan syndrome, childhood leukemias, and sporadic solid tumors. Virtual screening combined with experimental assays was performed to identify inhibitors of SHP2 from a database of natural products. This effort led to the identification of cryptotanshinone as an inhibitor of SHP2. Cryptotanshinone inhibited SHP2 with an IC50 of 22.50 μM. Fluorescence titration experiments confirmed that it directly bound to SHP2. Enzymatic kinetic analyses showed that cryptotanshinone was a mixed-type and irreversible inhibitor. This drug was further verified for its ability to block SHP2-mediated cell signaling and cellular functions. Furthermore, mouse myeloid progenitors and patient leukemic cells with the activating mutation E76K in PTPN11 were found to be sensitive to this inhibitor. Since cryptotanshinone is used to treat cardiovascular diseases in Asian countries, this drug has a potential to be used directly or to be further developed to treat PTPN11-associated malignancies.
PTPN11（编码 SHP2 磷酸酶）的激活突变与诺南综合征、儿童白血病和散发性实体肿瘤有关。通过虚拟筛选和实验检测，从天然产物数据库中鉴定出 SHP2 的抑制剂。这项工作导致鉴定出隐丹参酮为 SHP2 的抑制剂。隐丹参酮对 SHP2 的抑制作用的 IC50 为 22.50 μM。荧光滴定实验证实它直接与 SHP2 结合。酶动力学分析表明，隐丹参酮是一种混合型和不可逆抑制剂。该药物进一步验证了其阻断 SHP2 介导的细胞信号转导和细胞功能的能力。此外，具有 PTPN11 中激活突变 E76K 的小鼠髓系祖细胞和患者白血病细胞对该抑制剂敏感。由于隐丹参酮在亚洲国家用于治疗心血管疾病，因此该药物具有直接使用或进一步开发用于治疗 PTPN11 相关恶性肿瘤的潜力。
