2-Thiazolylimino/Heteroarylimino-5-arylidene-4-thiazolidinones as New Agents with SHP-2 Inhibitory Action
- 15 August 2008
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 51 (17), 5221-5228
- https://doi.org/10.1021/jm8004306
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.Keywords
This publication has 33 references indexed in Scilit:
- Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transductionHuman Molecular Genetics, 2006
- Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human DiseaseAmerican Journal of Human Genetics, 2006
- Diverse Biochemical Properties of Shp2 MutantsJournal of Biological Chemistry, 2005
- Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemiaBlood, 2004
- The ‘Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signalingTrends in Biochemical Sciences, 2003
- Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemiaNature Genetics, 2003
- Grouping of Multiple-Lentigines/LEOPARD and Noonan Syndromes on the PTPN11 GeneAmerican Journal of Human Genetics, 2002
- PTPN11 mutations in LEOPARD syndromeJournal of Medical Genetics, 2002
- Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndromeNature Genetics, 2001
- Hypertelorism With Turner PhenotypeAmerican Journal of Diseases of Children, 1968