title: 2-Thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones as new agents with SHP-2 inhibitory action.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University, Thessaloniki 54124, Greece. geronik@pharm.auth.gr
authors.forename: A
authors.initials: A
authors.lastname: Geronikaki
authors.forename: P
authors.initials: P
authors.lastname: Eleftheriou
authors.forename: P
authors.initials: P
authors.lastname: Vicini
authors.forename: I
authors.initials: I
authors.lastname: Alam
authors.forename: A
authors.initials: A
authors.lastname: Dixit
authors.forename: A K
authors.initials: AK
authors.lastname: Saxena
mesh_terms: D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D045162:Thiazolidinediones; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11