Development of tyrosine phosphatase SHP-2 inhibitors

酪氨酸磷酸酶SHP-2抑制剂的开发

• 批准号: 7056591
• 负责人: OLGUN GUVENCH
• 金额: $ 5.4万
• 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/7056591
• 关键词: Chordata; acute lymphocytic leukemia; gene mutation; information systems; lead; leukemia; play; protein tyrosine phosphatase; receptor; role; small molecule; syndrome; water

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发挥作用。 SHP-2 由两个连续的 Src 同源 2 (SH2) 结构域和一个磷酸酶结构域组成，通过 N 端 SH2 结构域与磷酸酶结构域的结合实现自我抑制。这两个结构域的结合界面处导致自我抑制丧失的突变与急性淋巴细胞白血病、幼年型粒单核细胞白血病、急性单核细胞白血病以及发育性疾病努南综合征相关。拟议工作的具体目标是：1）使用计算机数据库筛选来识别具有作为 SHP-2 磷酸酶活性抑制剂潜力的小分子，包括开发一种在对接过程中包含桥接水的新方法； 2) 通过体外磷酸酶测定选择目标1中鉴定的具有所需生物活性的化合物； 3) 系统地修改目标 2 中确定的先导化合物，以进一步提高其 SHP-2 磷酸酶抑制的功效。所开发的抑制剂将作为研究工具和白血病和努南综合征治疗方法的潜在先驱。