Abstract

This project proposes the identification, optimization, and characterization of small molecules that affect protein-protein and protein-DNA interactions in the Myc and the beta-catenin-LEF networks. The project also proposes identification and development of anticancer compounds from novel combinatorial chemical libraries. The work is based on discoveries made during the past funding cycle which include the identification of the first small molecule inhibitors of Myc-Max dimerization, inhibitors of LEF-dependent transcription, and compounds that interfere with the growth of cancer cells. The project depends on strong collaboration with the laboratory of Dr. Boger in the area of chemistry and with Dr. Cheresh in the area of animal testing. The following are the specific aims: (1) Identify and characterize small molecules that inhibit Myc-Max dimerization. (2) Identify and characterize small molecules that stabilize interaction of Myc network proteins. (3) Identify and characterize small molecules that specifically inhibit LEF-dependent transcription. (4) Screen primary and analog combinatorial chemical libraries for compounds that are selectively active against cancer cells and characterize these compounds.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA078045-07
Application #
7062975
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
7
Fiscal Year
2005
Total Cost
$174,389
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