Development of tyrosine phosphatase SHP-2 inhibitors

描述(申请人提供)：非受体蛋白酪氨酸磷酸酶SHP-2是脊椎动物中一个关键的细胞信号分子，在正常发育和造血过程中发挥作用。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-末端SH2结构域与磷酸酶结构域的结合而自我抑制。这两个区域结合界面的突变导致自我抑制功能丧失，与急性淋巴细胞白血病、幼年性单核细胞白血病、急性单核细胞白血病以及发育性疾病Noonan综合征有关。拟议工作的具体目标是：1)利用电子数据库筛选，包括开发一种新的方法，在对接过程中包括桥水，以确定具有潜在抑制SHP-2磷酸酶活性的小分子；2)通过体外磷酸酶检测，选择在目标1中确定的具有理想生物活性的那些化合物；以及3)从目标2系统地修饰已确定的先导化合物，以进一步提高其对SHP-2磷酸酶抑制的效果。开发的抑制剂将作为白血病和Noonan综合征治疗的研究工具和潜在先驱。

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.