Development of tyrosine phosphatase SHP-2 inhibitors

酪氨酸磷酸酶SHP-2抑制剂的开发

• 批准号: 7451063
• 负责人: OLGUN GUVENCH
• 金额: $ 5.8万
• 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/7451063
• 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(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。

项目成果

CHARMM additive all-atom force field for aldopentofuranoses, methyl-aldopentofuranosides, and fructofuranose.

• DOI: 10.1021/jp905496e
• 发表时间: 2009-09-17
• 期刊: The journal of physical chemistry. B
• 作者: Hatcher E;Guvench O;Mackerell AD
• 通讯作者: Mackerell AD

CHARMM Additive All-Atom Force Field for Acyclic Polyalcohols, Acyclic Carbohydrates and Inositol.

• DOI: 10.1021/ct9000608
• 发表时间: 2009-04-27
• 期刊: JOURNAL OF CHEMICAL THEORY AND COMPUTATION
• 影响因子: 5.5
• 作者: Hatcher, Elizabeth R.;Guvench, Olgun;MacKerell, Alexander D., Jr.
• 通讯作者: MacKerell, Alexander D., Jr.

Identification of small molecular weight inhibitors of Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) via in silico database screening combined with experimental assay.

• DOI: 10.1021/jm800229d
• 发表时间: 2008-12-11
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Yu WM;Guvench O;Mackerell AD;Qu CK
• 通讯作者: Qu CK

CHARMM Additive All-Atom Force Field for Glycosidic Linkages between Hexopyranoses.

• DOI: 10.1021/ct900242e
• 发表时间: 2009-08-20
• 期刊: JOURNAL OF CHEMICAL THEORY AND COMPUTATION
• 影响因子: 5.5
• 作者: Guvench, Olgun;Hatcher, Elizabeth;Venable, Richard M.;Pastor, Richard W.;MacKerell, Alexander D., Jr.
• 通讯作者: MacKerell, Alexander D., Jr.