Abstract

Efforts are focused on the design, synthesis and evaluation of polypeptides andconformationally constrained peptidomimetics that are targeted to inhibit, orotherwise modulate key cellular signal transduction processes. Our goal is todevelop therapeutic agents that are selective in inhibiting the oncogenic cellproliferative signal, or to boost the effectiveness of tumor suppressor genes.Our major research area is concerned with developing inhibitors of the rasoncogenic signaling pathway at the c-erbB2 growth factor receptor interactionsite with the Grb2 adaptor protein. Based on a phage library based cyclicprototype peptide, we developed several redox-stable analogs that boundselectively to the Grb2-SH2 domain protein at high nanomolar concentrations.Significantly, these agents inhibited the growth factor receptor associationin cell homogenates of breast cancer cells. Cell permeabilized analogs alsoinhibited MAP kinase activation in intact cancer cells. These novel inhibitorsare non-phosphorylated and do not contain phosphate mimicking groups, and areexpected to be constitutively active in cells. Inactivation of the c-erbB2receptor initiated signaling has potential therapeutic applications, mostnotably in the management of breast cancer.Good progress has been made in several related project areas. These include: 1./ Studies on the mechanism of action of the active site segments of Cdkinhibitory proteins, p21(Waf1/Cip1) and p16(INK4A); 2./ design of cyclicconformationally rigid peptides that inhibit Matriptase, an epithelial cellsurface derived matrix protease that has a potential function in breast cancercell metastasis; and 3./ development of proteolytically stable peptide analogsthat serve as novel HIV integrase enzyme inhibitors, as model compounds foranti-HIV therapeutics design. - antiproliferative agents, cell cycle inhibitors, peptide conformation, peptide synthesis, peptides, SH2 domain, Signal Transduction, peptidomimetics, - Neither Human Subjects nor Human Tissues

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC007354-06
Application #
6289188
Study Section
Special Emphasis Panel (LMC)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Sun, Haiying; Nikolovska-Coleska, Zaneta; Chen, Jianyong et al. (2005) Structure-based design, synthesis and biochemical testing of novel and potent Smac peptido-mimetics. Bioorg Med Chem Lett 15:793-7
Koehler, Niklas K U; Yang, Chao-Yie; Varady, Judith et al. (2004) Structure-based discovery of nonpeptidic small organic compounds to block the T cell response to myelin basic protein. J Med Chem 47:4989-97
Sun, Haiying; Nikolovska-Coleska, Zaneta; Yang, Chao-Yie et al. (2004) Structure-based design of potent, conformationally constrained Smac mimetics. J Am Chem Soc 126:16686-7
Nikolovska-Coleska, Zaneta; Wang, Renxiao; Fang, Xueliang et al. (2004) Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization. Anal Biochem 332:261-73
Krajewski, Krzysztof; Marchand, Christophe; Long, Ya-Qiu et al. (2004) Synthesis and HIV-1 integrase inhibitory activity of dimeric and tetrameric analogs of indolicidin. Bioorg Med Chem Lett 14:5595-8
Sun, Haiying; Nikolovska-Coleska, Zaneta; Yang, Chao-Yie et al. (2004) Structure-based design, synthesis, and evaluation of conformationally constrained mimetics of the second mitochondria-derived activator of caspase that target the X-linked inhibitor of apoptosis protein/caspase-9 interaction site. J Med Chem 47:4147-50
Nikolovska-Coleska, Zaneta; Xu, Liang; Hu, Zengjian et al. (2004) Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem 47:2430-40
Song, Yan-Li; Roller, Peter P; Long, Ya-Qiu (2004) Development of l-3-aminotyrosine suitably protected for the synthesis of a novel nonphosphorylated hexapeptide with low-nanomolar Grb2-SH2 domain-binding affinity. Bioorg Med Chem Lett 14:3205-8
Li, Peng; Peach, Megan L; Zhang, Manchao et al. (2003) Structure-based design of thioether-bridged cyclic phosphopeptides binding to Grb2-SH2 domain. Bioorg Med Chem Lett 13:895-9
Krajewski, Krzysztof; Long, Ya-Qiu; Marchand, Christophe et al. (2003) Design and synthesis of dimeric HIV-1 integrase inhibitory peptides. Bioorg Med Chem Lett 13:3203-5

Showing the most recent 10 out of 15 publications