Abstract

This is Core B of the Program """"""""Combinatorial Approaches for Novel Anti- cancer Agents,"""""""" a multidisciplinary effort to employ chemical diversity, high throughput and smart assays to anti-tumor drug discovery. In this Core, computational chemistry and chemical data base management will be used to analyze the structure-activity relationships of synthetic combinatorial libraries of phosphatase inhibitors and anti-tubulin compounds, leading to both mechanistic and structural insights for the optimization of anti-cancer chemotherapeutic activity. This strategy will allow for the identification and comparison of the structural and physicochemical features required for in vitro cell-free biochemical, in vitro tumor cell line, and in vivo anti-tumor activity. During the Program, Core B will build and utilize hierarchical SAR/QSAR models pertaining to the individual molecular targets, anti-proliferative activity towards cancer cell lines, and activity towards solid tumors. These activities will be optimized in order to discover selective, highly efficacious, pre-clinical chemotherapeutic agents with anti-tumor activity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA078039-03
Application #
6300631
Study Section
Project Start
2000-03-01
Project End
2001-02-28
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
3
Fiscal Year
2000
Total Cost
$193,832
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Type
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

McCabe, Stephanie R; Wipf, Peter (2016) Total synthesis, biosynthesis and biological profiles of clavine alkaloids. Org Biomol Chem 14:5894-913
George Rosenker, Kara M; Paquette, William D; Johnston, Paul A et al. (2015) Synthesis and biological evaluation of 3-aminoisoquinolin-1(2H)-one based inhibitors of the dual-specificity phosphatase Cdc25B. Bioorg Med Chem 23:2810-8
Korotchenko, Vasiliy N; Saydmohammed, Manush; Vollmer, Laura L et al. (2014) In vivo structure-activity relationship studies support allosteric targeting of a dual specificity phosphatase. Chembiochem 15:1436-45
Guo, Jianxia; Clausen, Dana M; Beumer, Jan H et al. (2013) In vitro cytotoxicity, pharmacokinetics, tissue distribution, and metabolism of small-molecule protein kinase D inhibitors, kb-NB142-70 and kb-NB165-09, in mice bearing human cancer xenografts. Cancer Chemother Pharmacol 71:331-44
Salum, Lívia B; Altei, Wanessa F; Chiaradia, Louise D et al. (2013) Cytotoxic 3,4,5-trimethoxychalcones as mitotic arresters and cell migration inhibitors. Eur J Med Chem 63:501-10
Wang, Y; Lazo, J S (2012) Metastasis-associated phosphatase PRL-2 regulates tumor cell migration and invasion. Oncogene 31:818-27
Arora, Reety; Shuda, Masahiro; Guastafierro, Anna et al. (2012) Survivin is a therapeutic target in Merkel cell carcinoma. Sci Transl Med 4:133ra56
Kitchens, Carolyn A; McDonald, Peter R; Shun, Tong Ying et al. (2011) Identification of chemosensitivity nodes for vinblastine through small interfering RNA high-throughput screens. J Pharmacol Exp Ther 339:851-8
Vollmer, Laura L; Jiménez, Maria; Camarco, Daniel P et al. (2011) A simplified synthesis of novel dictyostatin analogues with in vitro activity against epothilone B-resistant cells and antiangiogenic activity in zebrafish embryos. Mol Cancer Ther 10:994-1006
Hopkins, Chad D; Schmitz, John C; Chu, Edward et al. (2011) Total synthesis of (-)-CP2-disorazole C1. Org Lett 13:4088-91

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