Development of tyrosine phosphatase SHP-2 inhibitors

酪氨酸磷酸酶SHP-2抑制剂的开发

• 批准号: 7271319
• 负责人: OLGUN GUVENCH
• 金额: $ 5.59万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271319
• 关键词: Accounting; Acute Lymphocytic Leukemia; Acute monocytic leukemia; Binding; Biological; Biological Assay; Chemistry; Computer Simulation; Databases; Development; Disease; Docking; Doctor of Medicine; Doctor of Philosophy; Educational process of instructing; Faculty; HC phosphatase; Hematopoiesis; In Vitro; Juvenile Myelomonocytic Leukemia; Lead; Mediating; Medicine; Mutation; N-terminal; Noonan Syndrome; PTPN11 gene; Phosphoric Monoester Hydrolases; Positioning Attribute; Process; Protein Tyrosine Phosphatase; Proteins; Research; Role playing therapy; Screening procedure; Signal Transduction; Signaling Molecule; Therapeutic; Training; Vertebrates; Water; Work; drug discovery; experience; human PTPRT protein; inhibitor/antagonist; leukemia; method development; novel strategies; phosphatase inhibitor; small molecule; tool

DESCRIPTION (provided by applicant): The non-receptor protein tyrosine phosphatase SHP-2 is a key cell-signaling molecule in vertebrates that plays roles in normal development and hematopoiesis. Composed of two successive Src homology 2 (SH2) domains followed by a phosphatase domain, SHP-2 is self-inhibited by binding of the N-terminal SH2 domain to the phosphatase domain. Mutations at the binding interface of these two domains that cause loss of self- inhibition are associated with acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, and acute monocytic leukemia as well as the developmental disease Noonan syndrome. The specific aims of the proposed work are: 1) identify small molecules with the potential to act as inhibitors of SHP-2 phosphatase activity using in silico database screening, including development of a novel approach to include bridging waters in the docking process; 2) select those compounds identified in aim 1 with the desirable biological activity through in vitro phosphatase assays; and 3) systematically modify the identified lead compounds from aim 2 to further increase the efficacy of their SHP-2 phosphatase inhibition. The developed inhibitors will serve as research tools and potential precursors to therapeutics for leukemia and Noonan syndrome.

描述（由申请人提供）：非受体蛋白酪氨酸磷酸酶SHP-2是脊椎动物中的关键细胞信号分子，在正常发育和造血中起着作用。由两个连续的SRC同源性2（SH2）结构域组成，然后由磷酸酶结构域组成，SHP-2通过N端SH2结构域与磷酸酶结构域的结合而自抑制。这两个结构域的结合界面的突变与急性淋巴细胞白血病，青少年脊髓细胞性白血病和急性单核细胞性白血病以及发育性疾病Noonan综合征有关。拟议工作的具体目的是：1）确定使用硅数据库筛选中使用SHP-2磷酸酶活性抑制剂的潜力的小分子，包括开发了一种新的方法来包括在停靠过程中桥接水域； 2）选择AIM 1中鉴定出的那些化合物，具有通过体外磷酸酶测定的理想生物学活性； 3）系统地修改AIM 2的已识别铅化合物，以进一步提高其SHP-2磷酸酶抑制的功效。开发的抑制剂将作为白血病和Noonan综合征治疗剂的研究工具和潜在的前体。