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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA119771-01
Application #
7056591
Study Section
Special Emphasis Panel (ZRG1-F04B (20))
Program Officer
Jakowlew, Sonia B
Project Start
2006-07-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$53,992
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Hatcher, Elizabeth; Guvench, Olgun; Mackerell, Alexander D (2009) CHARMM additive all-atom force field for aldopentofuranoses, methyl-aldopentofuranosides, and fructofuranose. J Phys Chem B 113:12466-76
Hatcher, Elizabeth; Guvench, Olgun; Mackerell Jr, Alexander D (2009) CHARMM Additive All-Atom Force Field for Acyclic Polyalcohols, Acyclic Carbohydrates and Inositol. J Chem Theory Comput 5:1315-1327
Yu, Wen-Mei; Guvench, Olgun; Mackerell, Alexander D et al. (2008) 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. J Med Chem 51:7396-404
Guvench, Olgun; MacKerell Jr, Alexander D (2008) Comparison of protein force fields for molecular dynamics simulations. Methods Mol Biol 443:63-88
Guvench, Olgun; Qu, Cheng-Kui; MacKerell Jr, Alexander D (2007) Tyr66 acts as a conformational switch in the closed-to-open transition of the SHP-2 N-SH2-domain phosphotyrosine-peptide binding cleft. BMC Struct Biol 7:14