Development of tyrosine phosphatase SHP-2 inhibitors

描述（由申请人提供）：非受体蛋白酪氨酸磷酸酶SHP-2是脊椎动物中关键的细胞信号分子，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，SHP-2通过n端SH2结构域与磷酸酶结构域结合而自我抑制。这两个结构域结合界面的突变导致自我抑制丧失，与急性淋巴细胞白血病、青少年髓细胞白血病、急性单核细胞白血病以及发育性疾病努南综合征有关。所提出的工作的具体目标是：1)使用计算机数据库筛选识别有可能作为SHP-2磷酸酶活性抑制剂的小分子，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中鉴定的具有理想生物活性的化合物；3)系统修饰目的2中鉴定的先导化合物，进一步提高其抑制SHP-2磷酸酶的功效。开发的抑制剂将作为研究工具和潜在的前体治疗白血病和努南综合征。

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.