Abstract

The development and application of the solution-phase synthesis of combinatorial libraries for screening in novel assays designed to identify new agents for the treatment of cancer are detailed. In the past efforts, over 40,000 compounds have been prepared and archived in existing libraries and this will be increased to 1,000,000 compounds under the present grant. Included in this library and as part of its expansion are templates and mimetics that target protein-protein or protein-DNA interactions. The screening of the current libraries and the subsequent lead optimization have provided (1) the first angiogenesis inhibitors exhibiting in vivo antitumor activity based on inhibition of MMP2 binding to integrin alphavbeta3, (2) the first small molecule inhibitors of Myc-Max dimerization that inhibit c-Myc-induced cell transformation, (3) the first inhibitors of intracellular Paxillin/alpha4 binding which serve to inhibit cell migration, (4) relatively small EPO agonists that act by promoting EPO receptor dimerization, and (5) two classes of inhibitors of LEF-1/beta-catenin mediated gene transcription. Continued efforts on these targets will complement new studies on additional targets.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA078045-08
Application #
7183580
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
8
Fiscal Year
2006
Total Cost
$186,328
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Gochin, Miriam; Whitby, Landon R; Phillips, Aaron H et al. (2013) NMR-assisted computational studies of peptidomimetic inhibitors bound in the hydrophobic pocket of HIV-1 glycoprotein 41. J Comput Aided Mol Des 27:569-82
Whitby, Landon R; Boger, Dale L (2012) Comprehensive peptidomimetic libraries targeting protein-protein interactions. Acc Chem Res 45:1698-709
Hart, Jonathan R; Liao, Lujian; Yates 3rd, John R et al. (2011) Essential role of Stat3 in PI3K-induced oncogenic transformation. Proc Natl Acad Sci U S A 108:13247-52
Whitby, Landon R; Ando, Yoshio; Setola, Vincent et al. (2011) Design, synthesis, and validation of a ýý-turn mimetic library targeting protein-protein and peptide-receptor interactions. J Am Chem Soc 133:10184-94
Shields, D J; Murphy, E A; Desgrosellier, J S et al. (2011) Oncogenic Ras/Src cooperativity in pancreatic neoplasia. Oncogene 30:2123-34
Murphy, Eric A; Majeti, Bharat K; Mukthavaram, Rajesh et al. (2011) Targeted nanogels: a versatile platform for drug delivery to tumors. Mol Cancer Ther 10:972-82
Hart, Jonathan Ross; Liao, Lujian; Ueno, Lynn et al. (2011) Protein expression profiles of C3H 10T1/2 murine fibroblasts and of isogenic cells transformed by the H1047R mutant of phosphoinositide 3-kinase (PI3K). Cell Cycle 10:971-6
Kolesnichenko, Marina; Vogt, Peter K (2011) Understanding PLZF: two transcriptional targets, REDD1 and smooth muscle ?-actin, define new questions in growth control, senescence, self-renewal and tumor suppression. Cell Cycle 10:771-5
Thomas, Celestine J; Casquilho-Gray, Hedi E; York, Joanne et al. (2011) A specific interaction of small molecule entry inhibitors with the envelope glycoprotein complex of the Junín hemorrhagic fever arenavirus. J Biol Chem 286:6192-200
Sun, Minghao; Hart, Jonathan R; Hillmann, Petra et al. (2011) Addition of N-terminal peptide sequences activates the oncogenic and signaling potentials of the catalytic subunit p110? of phosphoinositide-3-kinase. Cell Cycle 10:3731-9

Showing the most recent 10 out of 85 publications