SHP-2, a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene, mediates cell signaling by growth factors and cytokines via the RAS/MAP kinase pathway. Somatic mutations in PTPN11 gene account for approximately 18% of juvenile myelomonocytic leukemia (JMML) patients. Moreover, SHP-2 mutations leading to continuously active enzyme were found in more than 50% of Noonan syndrome patients and are considered to be responsible for the high tendency of these patients to juvenile leukemias and other cancer types. Recently SHP-2 became a new drug target, but till now little has been done in this field. In the present study, 17 2-thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones divided into three series of derivatives bearing thiazole-, benzo[d]thiazole-, and benzo[d]isothizole rings were tested for SHP-2 inhibitory activity. Most of the compounds were good SHP-2 inhibitors. Benzo[d]thiazole derivatives exhibited the best inhibitory action. Docking studies revealed that hydrophobic interactions and hydrogen bond formation stabilize enzyme-inhibitor complex.
2-THIAZOLYLIMINO/ HETEROARYLIMINO-5-ARYLIDENE-4-THIAZOLIDINONES AS NEW AGENTS WITH SHP-2 INHIBITORY ACTION / GERONIKAKI A.; ELEFTHERIOU P.T.; VICINI P.; DIXIT A.; SAXENA A.; ALAM I.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 51(2008), pp. 5221-5228. [10.1021/jm8004306]