A Concerted Chemical, Biophysical and Molecular Biological Attack of Intracellul*

Summary

Principal Investigator: Steven L McKnight
Affiliation: University of Texas Southwestern Medical Center
Country: USA
Abstract: This Program Project Grant (PPG) competitive renewal application seeks to build on its success of the past four years. We will continue to probe the modes of action of unique natural products showing promising anticancer activity, thereby fostering efforts to move such molecules towards clinical testing. The application further seeks to discover and characterize synthetic compounds that selectively agonize or antagonize biological pathways relevant to human cancer. Four interrelated projects are proposed. The first will employ the tools of biochemistry, molecular biology and genetics to uncover the molecular targets of natural products showing potent and selective cytotoxic activity. The second project seeks to resolve the enigmatic involvement of ornthine amino transferase (OAT) in the spindle assembly pathway of transformed cells, and further validate this molecular target for the development of anti-cancer drugs. The third project outlines a comprehensive series of experiments aimed at determining the basis for single agent toxicity of a synthetic mimic of Smac on tumor necrosis factor-secreting cancer cells. The fourth project seeks to identify and validate synthetic organic chemicals capable of either activating or inhibiting the hypoxia response pathway as a means of treating either anemia or cancer. All four programs will enlist the combined use of chemical, biochemical, genetic and molecular biological research. Each of the four projects will further rely on three technology cores sophisticated in the use of 1) high throughput screening (HTS Core), 2) small animal pharmacology (Pharmacology Core), and 3) chemical synthesis for the purposes of structure-activity relationship (SAR) studies, compound re-supply and drug formulation (Chemistry Core). All three technology cores are unique to our PPG team in the context of the sponsoring institution (UT Southwestern Medical Center), and are vital to the goals of the proposed research. Beyond serving as financial support crucial for the proposed research objectives, continued funding of this PPG is vital for sustained scientific synergy at the interfaces of chemical, biochemical, molecular biological and biophysical research at the host institution.
Funding Period: 2002-09-01 - 2012-07-31
more information: NIH RePORT

Top Publications

  1. pmc Evaluating the potential of vacuolar ATPase inhibitors as anticancer agents and multigram synthesis of the potent salicylihalamide analog saliphenylhalamide
    Sylvain Lebreton
    Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390 9038, USA
    Bioorg Med Chem Lett 18:5879-83. 2008
  2. pmc Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor
    Thomas H Scheuermann
    Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 106:450-5. 2009
  3. ncbi Identification and optimization of protein domains for NMR studies
    Paul B Card
    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Methods Enzymol 394:3-16. 2005
  4. doi Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha
    Sudan He
    Graduate Program, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
    Cell 137:1100-11. 2009
  5. pmc Structure-activity relationship studies of small-molecule inhibitors of Wnt response
    Jianming Lu
    Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
    Bioorg Med Chem Lett 19:3825-7. 2009
  6. pmc Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer
    Baozhi Chen
    Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA
    Nat Chem Biol 5:100-7. 2009
  7. doi Stereoselective synthesis of acetoacetate-derived enol triflates
    David Babinski
    Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390 9038, USA
    Org Lett 10:2901-4. 2008
  8. doi TNF-alpha induces two distinct caspase-8 activation pathways
    Lai Wang
    Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
    Cell 133:693-703. 2008
  9. ncbi High-throughput screen for small molecule inhibitors of Mint1-PDZ domains
    Xuesong Chen
    Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390 9040, USA
    Assay Drug Dev Technol 5:769-83. 2007
  10. ncbi Hypoxia-inducible factors Per/ARNT/Sim domains: structure and function
    Thomas H Scheuermann
    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
    Methods Enzymol 435:3-24. 2007

Scientific Experts

  • PAUL RICK
  • Kevin H Gardner
  • Thomas H Scheuermann
  • Noelle S Williams
  • Lai Wang
  • Xiaodong Wang
  • Michael G Roth
  • Richard K Bruick
  • Paul B Card
  • Baozhi Chen
  • Jianming Lu
  • Jinsong Yang
  • Lei Zhang
  • Zhiqiang Ma
  • James F Amatruda
  • Lawrence Lum
  • Sudan He
  • Chih Wei Fan
  • Jason Key
  • Chuo Chen
  • Fenghe Du
  • Sylvain Lebreton
  • Shuguang Wei
  • Jamie C Longgood
  • David Babinski
  • Doug E Frantz
  • Xuesong Chen
  • Sean L Petersen
  • David Padron
  • Patrick G Harran
  • Junko Kajimura
  • Iryna Zubovych
  • Paul J A Erbel
  • Chowdhury Faiz Hossain
  • Wei Tang
  • Tao Wang
  • Jessica Kilgore
  • Jen Chieh Hsieh
  • Valerie Daggett
  • Peter C Anderson
  • Lin Miao
  • Wayne Hao
  • Yan Guo
  • Michael E Dodge
  • Mischa Machius
  • Liping Zhao
  • Diana R Tomchick
  • Janis Jaunbergs
  • Omid Soltani
  • Jef K De Brabander
  • Deborah A Ferguson
  • John D Minna
  • Anthony W G Burgett
  • Llya Bezprozvanny
  • Jerry W Shay
  • Patrick Harran
  • Adi F Gazdar
  • Carolyn Michnoff
  • Lin Li
  • Asligul Yalcin-Chin
  • Mitsuo Sato
  • Ashley S Atkins
  • Michael Peyton
  • John Minna
  • Steven L McKnight
  • Arifur Rahman
  • Thomas Doundoulakis
  • Matthew R Evans
  • James Hsu
  • Ameeta K Agarwal
  • Dale G Nagle
  • Joseph A Garcia
  • Kaleem A Mohammed
  • Yu Dong Zhou
  • Yong Pil Kim
  • Kan Ding
  • Scott R Baerson

Detail Information

Publications19

  1. pmc Evaluating the potential of vacuolar ATPase inhibitors as anticancer agents and multigram synthesis of the potent salicylihalamide analog saliphenylhalamide
    Sylvain Lebreton
    Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390 9038, USA
    Bioorg Med Chem Lett 18:5879-83. 2008
    ..To further validate the potential of V-ATPase inhibitors as leads for cancer chemotherapy, we developed a multigram synthesis of the potent salicylihalamide analog saliphenylhalamide...
  2. pmc Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor
    Thomas H Scheuermann
    Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 106:450-5. 2009
    ..Given the essential role of PAS domains in forming active HIF heterodimers, these results suggest a presently uncharacterized ligand-mediated mechanism for regulating HIF2 activity in endogenous and clinical settings...
  3. ncbi Identification and optimization of protein domains for NMR studies
    Paul B Card
    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Methods Enzymol 394:3-16. 2005
    ..Here we present a variety of computational and experimental methods developed for these purposes and show that great care must often be taken in the design of constructs intended for NMR-based investigations...
  4. doi Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha
    Sudan He
    Graduate Program, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
    Cell 137:1100-11. 2009
    ..These data indicate RIP3 as the determinant for cellular necrosis in response to TNF-alpha family of death-inducing cytokines...
  5. pmc Structure-activity relationship studies of small-molecule inhibitors of Wnt response
    Jianming Lu
    Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
    Bioorg Med Chem Lett 19:3825-7. 2009
    ..Herein, we present the results of structure-activity relationship studies of these compounds...
  6. pmc Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer
    Baozhi Chen
    Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA
    Nat Chem Biol 5:100-7. 2009
    ..The signal transduction mechanisms shown here to be chemically tractable additionally contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals...
  7. doi Stereoselective synthesis of acetoacetate-derived enol triflates
    David Babinski
    Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390 9038, USA
    Org Lett 10:2901-4. 2008
    ....
  8. doi TNF-alpha induces two distinct caspase-8 activation pathways
    Lai Wang
    Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
    Cell 133:693-703. 2008
    ..These findings revealed that TNF-alpha is able to induce apoptosis via two distinct caspase-8 activation pathways that are differentially regulated by cIAP1/2 and c-FLIP...
  9. ncbi High-throughput screen for small molecule inhibitors of Mint1-PDZ domains
    Xuesong Chen
    Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390 9040, USA
    Assay Drug Dev Technol 5:769-83. 2007
    ..The assays described provided an example of HTS for a small molecule inhibitor of Mint-PDZ domain that can be easily adapted to other PDZ domain-mediated interactions...
  10. ncbi Hypoxia-inducible factors Per/ARNT/Sim domains: structure and function
    Thomas H Scheuermann
    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
    Methods Enzymol 435:3-24. 2007
    ..This review highlights strategies for the biophysical and biochemical characterization of the PAS domains found within both HIF subunits and provides a platform for future efforts to exploit these domains in therapeutic settings...
  11. pmc Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis
    Sean L Petersen
    Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
    Cancer Cell 12:445-56. 2007
    ..In response to autocrine TNFalpha signaling, the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis...
  12. pmc Epidermal growth factor receptors with tyrosine kinase domain mutations exhibit reduced Cbl association, poor ubiquitylation, and down-regulation but are efficiently internalized
    David Padron
    Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
    Cancer Res 67:7695-702. 2007
    ..Thus, the mutations that altered signaling also decreased the interaction of EGFRs with the mechanisms responsible for endosomal sorting...
  13. pmc Therapeutic anticancer efficacy of a synthetic diazonamide analog in the absence of overt toxicity
    Noelle S Williams
    Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 104:2074-9. 2007
    ..These observations raise the possibility that AB-5 may have clinical utility for cancer therapy under conditions largely devoid of chemotherapeutic toxicity and suggest that further preclinical evaluation of AB-5 is warranted...
  14. pmc A missense mutation in Caenorhabditis elegans prohibitin 2 confers an atypical multidrug resistance
    Iryna Zubovych
    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 9038, USA
    Proc Natl Acad Sci U S A 103:15523-8. 2006
    ..Thus, prohibitin 2 is implicated in a previously uncharacterized pathway of multidrug resistance...
  15. pmc O acetylation of the enterobacterial common antigen polysaccharide is catalyzed by the product of the yiaH gene of Escherichia coli K-12
    Junko Kajimura
    Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 4799
    J Bacteriol 188:7542-50. 2006
    ..Accordingly, we propose that this gene be designated wecH...
  16. ncbi Structural basis of ARNT PAS-B dimerization: use of a common beta-sheet interface for hetero- and homodimerization
    Paul B Card
    Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 8816, USA
    J Mol Biol 353:664-77. 2005
    ..With this information, we propose a model for the mode of multi-PAS domain interaction in bHLH-PAS transcriptional activation complexes...
  17. ncbi Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor
    Jinsong Yang
    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9038, USA
    J Biol Chem 280:36047-54. 2005
    ..Because disruption of individual PAS domains compromise HIF function independent of the mechanism of HIF induction, these data demonstrate the potential utility of targeting these domains for therapeutic applications...
  18. pmc Saururus cernuus lignans--potent small molecule inhibitors of hypoxia-inducible factor-1
    Chowdhury Faiz Hossain
    Department of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677 1848, USA
    Biochem Biophys Res Commun 333:1026-33. 2005
    ..In addition, preliminary structure-activity studies suggest specific structural requirements for this class of HIF-1 inhibitors...
  19. pmc Principles of ligand binding within a completely buried cavity in HIF2alpha PAS-B
    Jason Key
    Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390 8816, USA
    J Am Chem Soc 131:17647-54. 2009
    ..Finally, molecular dynamics simulations reveal conversion between open and closed conformations of the protein and pathways of ligand entry into the binding pocket...