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. pmc Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia
    Yang Liu
    Center for Autophagy Research, Departments of Internal Medicine, Biochemistry, and Microbiology, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390
    Proc Natl Acad Sci U S A 110:20364-71. 2013
  4. pmc Regulating the ARNT/TACC3 axis: multiple approaches to manipulating protein/protein interactions with small molecules
    Yirui Guo
    Departments of Biophysics, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 8816, USA
    ACS Chem Biol 8:626-35. 2013
  5. pmc Studies toward the unique pederin family member psymberin: structure-activity relationships, biochemical studies, and genetics identify the mode-of-action of psymberin
    Cheng Yang Wu
    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    J Am Chem Soc 134:18998-9003. 2012
  6. pmc Anthraquinones from a marine-derived Streptomyces spinoverrucosus
    Youcai Hu
    Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390 9038, USA
    J Nat Prod 75:1759-64. 2012
  7. pmc Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease
    Héctor De Jesús-Cortés
    Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 109:17010-5. 2012
  8. pmc Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis
    Rachel Tesla
    Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 109:17016-21. 2012
  9. pmc Obatoclax, saliphenylhalamide, and gemcitabine inhibit influenza a virus infection
    Oxana V Denisova
    Institute for Molecular Medicine Finland, FIMM, Helsinki, Finland
    J Biol Chem 287:35324-32. 2012
  10. pmc Enlightening molecular mechanisms through study of protein interactions
    Josep Rizo
    Department of Biophysics, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA
    J Mol Cell Biol 4:270-83. 2012

Scientific Experts

  • Lawrence Lum
  • Xin Qi
  • Andrew A Pieper
  • PAUL RICK
  • Youcai Hu
  • Kevin H Gardner
  • Noelle S Williams
  • Thomas H Scheuermann
  • Xiaodong Wang
  • John B Macmillan
  • Richard K Bruick
  • Jacinth Naidoo
  • Lai Wang
  • Michael G Roth
  • Jason Key
  • Doug E Frantz
  • Shuguang Wei
  • Jef K De Brabander
  • Joseph M Ready
  • Lorraine Morlock
  • Paul B Card
  • Steven L McKnight
  • Patrick G Harran
  • Sean L Petersen
  • Lei Zhang
  • Changguang Wang
  • Gelin Wang
  • Jamie Longgood
  • Lisa Melito
  • Rachel Tesla
  • Sandi Jo Estill
  • She Chen
  • Sudan He
  • Baozhi Chen
  • Jianming Lu
  • Iryna Zubovych
  • Jinsong Yang
  • Jamie L Rogers
  • Uttam K Tambar
  • Kenneth V Lawson
  • Yirui Guo
  • Lei Wang
  • Jessica A Kilgore
  • Bruce Posner
  • Yang Liu
  • James H Frederich
  • Xiaoguang Lei
  • Noelle Williams
  • Muhammed Yousufuddin
  • Samuel Peña-Llopis
  • Elisabeth D Martinez
  • Aaron G Legako
  • Josep Rizo
  • Pin Xu
  • Héctor De Jesús-Cortés
  • Cheng Yang Wu
  • Ende Pan
  • Sharanya Sivanand
  • Paula Huntington
  • Jordan Drawbridge
  • Oxana V Denisova
  • Stephanie Tran
  • Liming Sun
  • Ana Paula D M Espindola
  • Karen S MacMillan
  • Min Fang
  • Lin Li
  • Sarah Straud
  • Patrick Harran
  • Liping Zhao
  • Zhiqiang Ma
  • Chuo Chen
  • James F Amatruda
  • Chih Wei Fan
  • Joseph A Garcia
  • Fenghe Du
  • Michael Peyton
  • John D Minna
  • Sylvain Lebreton
  • Jamie C Longgood
  • David Babinski
  • Xuesong Chen
  • David Padron
  • Junko Kajimura
  • Chowdhury Faiz Hossain
  • Paul J A Erbel
  • Jianjun Chang
  • Michael A White
  • Ramnik J Xavier
  • Liying Zhang

Detail Information

Publications51

  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. pmc Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia
    Yang Liu
    Center for Autophagy Research, Departments of Internal Medicine, Biochemistry, and Microbiology, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390
    Proc Natl Acad Sci U S A 110:20364-71. 2013
    ..These findings have implications for understanding how cells die during certain stress conditions and how such cell death might be prevented...
  4. pmc Regulating the ARNT/TACC3 axis: multiple approaches to manipulating protein/protein interactions with small molecules
    Yirui Guo
    Departments of Biophysics, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 8816, USA
    ACS Chem Biol 8:626-35. 2013
    ..Overall, our data identify small molecule regulators for this important complex and highlight the utility of pursuing parallel strategies to develop protein/protein inhibitors...
  5. pmc Studies toward the unique pederin family member psymberin: structure-activity relationships, biochemical studies, and genetics identify the mode-of-action of psymberin
    Cheng Yang Wu
    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    J Am Chem Soc 134:18998-9003. 2012
    ..Unlike pederin and mycalamide, psymberin does not display irritant or blistering activity...
  6. pmc Anthraquinones from a marine-derived Streptomyces spinoverrucosus
    Youcai Hu
    Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390 9038, USA
    J Nat Prod 75:1759-64. 2012
    ..Galvaquinone B (2) was found to show epigenetic modulatory activity at 1.0 μM and exhibited moderate cytotoxicity against non-small-cell lung cancer (NSCLC) cell lines Calu-3 and H2887...
  7. pmc Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease
    Héctor De Jesús-Cortés
    Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 109:17010-5. 2012
    ..We propose that the chemical scaffold represented by P7C3 and P7C3A20 provides a basis for optimizing and advancing pharmacologic agents for the treatment of patients with PD...
  8. pmc Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis
    Rachel Tesla
    Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 109:17016-21. 2012
    ..We propose that the chemical scaffold represented by P7C3 and P7C3A20 may provide a basis for the discovery and optimization of pharmacologic agents for the treatment of ALS...
  9. pmc Obatoclax, saliphenylhalamide, and gemcitabine inhibit influenza a virus infection
    Oxana V Denisova
    Institute for Molecular Medicine Finland, FIMM, Helsinki, Finland
    J Biol Chem 287:35324-32. 2012
    ..Altogether, our results suggest that phase II obatoclax, investigational SaliPhe, and FDA/EMEA-approved gemcitabine represent potent antiviral agents...
  10. pmc Enlightening molecular mechanisms through study of protein interactions
    Josep Rizo
    Department of Biophysics, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA
    J Mol Cell Biol 4:270-83. 2012
    ..Overall, this research underlines the complexities involved in elucidating molecular mechanisms and how these mechanisms can depend critically on an interplay between strong and weak protein interactions...
  11. pmc A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma
    Sharanya Sivanand
    Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Sci Transl Med 4:137ra75. 2012
    ..The routine incorporation of models recapitulating the molecular genetics and drug sensitivities of human tumors into preclinical programs has the potential to improve oncology drug development...
  12. doi Small-molecule activation of the TRAIL receptor DR5 in human cancer cells
    Gelin Wang
    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
    Nat Chem Biol 9:84-9. 2013
    ..Thus, this study identified potential lead compounds for the development of small-molecule TRAIL mimics targeting DR5 for cancer therapy...
  13. pmc A mass balance approach for calculation of recovery and binding enables the use of ultrafiltration as a rapid method for measurement of plasma protein binding for even highly lipophilic compounds
    Changguang Wang
    Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
    J Pharm Biomed Anal 75:112-7. 2013
    ..The speed with which UF can be conducted additionally avoids changes in pH or compound loss that can occur with other methods. The mass balance approach to UF is thus a preferred method for rapid determination of PPB...
  14. pmc Template-constrained macrocyclic peptides prepared from native, unprotected precursors
    Kenneth V Lawson
    Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095
    Proc Natl Acad Sci U S A 110:E3753-60. 2013
    ..Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification. ..
  15. pmc Discoipyrroles A-D: isolation, structure determination, and synthesis of potent migration inhibitors from Bacillus hunanensis
    Youcai Hu
    Department of Biochemistry, Department of Cell Biology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390, United States
    J Am Chem Soc 135:13387-92. 2013
    ..Examination of the biosynthesis has led to the conclusion that the discoipyrroles are formed through a nonenzymatic process, leading to a one-pot total synthesis of 1. ..
  16. pmc A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth
    Lei Wang
    Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
    Nat Commun 4:2035. 2013
    ....
  17. pmc Identification of DNMT1 selective antagonists using a novel scintillation proximity assay
    Jessica A Kilgore
    Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
    J Biol Chem 288:19673-84. 2013
    ..To our knowledge, this work represents the first description of selective chemical inhibitors of the DNMT1 enzyme. ..
  18. pmc Modular access to complex prodiginines: total synthesis of (+)-roseophilin via its 2-azafulvene prototropisomer
    James H Frederich
    Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E Young Drive East, Los Angeles, California 90095 1569, USA
    J Am Chem Soc 135:3788-91. 2013
    ..Our route constructs the pyrrolophane motif via phosphoryl transfer-terminated macroaldolization and passes through a previously unexplored prototropic form of the natural product...
  19. pmc Allosteric inhibition of hypoxia inducible factor-2 with small molecules
    Thomas H Scheuermann
    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
    Nat Chem Biol 9:271-6. 2013
    ..These chemical tools establish the molecular basis for selective regulation of HIF-2, providing potential therapeutic opportunities to intervene in HIF-2-driven tumors, such as renal cell carcinomas...
  20. pmc Development of inhibitors of the PAS-B domain of the HIF-2α transcription factor
    Jamie L Rogers
    Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390 9038, United States
    J Med Chem 56:1739-47. 2013
    ..These results may serve as a foundation for discovering therapeutic agents that function by a novel mode of action. ..
  21. pmc Novel small molecules relieve prothymosin alpha-mediated inhibition of apoptosome formation by blocking its interaction with Apaf-1
    Xin Qi
    Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Biochemistry 49:1923-30. 2010
    ..Together, these studies would lead to novel and specific methods for the prevention, diagnosis, and treatment of human cancer...
  22. pmc Ammosamide D, an oxidatively ring opened ammosamide analog from a marine-derived Streptomyces variabilis
    Ende Pan
    Department of Biochemistry, Division of Chemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States
    Org Lett 14:2390-3. 2012
    ..Attempts at chemical conversion of ammosamide B to ammosamide D revealed that a strong chemical oxidant is required. Ammosamide D has modest cytotoxicity to the MIA PaCa-2 pancreatic cancer cell line...
  23. pmc Erythrolic acids A-E, meroterpenoids from a marine-derived Erythrobacter sp
    Youcai Hu
    Department of Biochemistry, Division of Chemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390 9038, USA
    J Org Chem 77:3401-7. 2012
    ..The unusual nature of the terpene side chain, we believe, involves an oxidation of a terminal methyl group to a carboxylic acid and subsequent Claisen condensation with acetyl-CoA...
  24. ncbi Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase
    Liming Sun
    National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China
    Cell 148:213-27. 2012
    ..These findings implicate MLKL as a key mediator of necrosis signaling downstream of the kinase RIP3...
  25. pmc Erythrazoles A-B, cytotoxic benzothiazoles from a marine-derived Erythrobacter sp
    Youcai Hu
    Department of Biochemistry, Division of Chemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
    Org Lett 13:6580-3. 2011
    ..Erythrazole B is cytotoxic to a panel of non-small cell lung cancer (NSCLC) cell lines, with IC(50) values of 1.5, 2.5, and 6.8 μM against H1325, H2122, and HCC366, respectively...
  26. pmc Chromomycin SA analogs from a marine-derived Streptomyces sp
    Youcai Hu
    Department of Biochemistry, Division of Chemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 9038, USA
    Bioorg Med Chem 19:5183-9. 2011
    ..Biological evaluation of chromomycin analogs for cytotoxicity against two non-small cell lung cancer (NSCLC) cell-lines, A549 and HCC44, demonstrated a decrease in cytotoxicity for the truncated sides chain chromomycin analogs...
  27. pmc Overcoming cancer cell resistance to Smac mimetic induced apoptosis by modulating cIAP-2 expression
    Sean L Petersen
    Howard Hughes Medical Institute and Department of Biochemistry and Hamon Center for Therapeutic Oncology Research and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 107:11936-41. 2010
    ..Using the PI3K inhibitor, LY294002, cIAP2 up-regulation was suppressed and resistance to Smac mimetics-induced apoptosis was also overcome...
  28. pmc Discovery of a proneurogenic, neuroprotective chemical
    Andrew A Pieper
    Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 9152, USA
    Cell 142:39-51. 2010
    ..Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging. PAPERCLIP:..
  29. pmc Inhibition of iron uptake is responsible for differential sensitivity to V-ATPase inhibitors in several cancer cell lines
    Sarah Straud
    Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America
    PLoS ONE 5:e11629. 2010
    ..SK-Mel-5 cells have increased production of reactive oxygen species and may be seeking to limit additional production of ROS by iron...
  30. doi The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway
    Min Fang
    Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 75390, USA
    Cell 143:711-24. 2010
    ..The growth of PTEN null cells is inhibited both in vitro and in mouse xenograft tumor models. ENTPD5 is therefore an integral part of the PI3K/PTEN regulatory loop and a potential target for anticancer therapy...
  31. pmc Development of proneurogenic, neuroprotective small molecules
    Karen S MacMillan
    Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390 9038, United States
    J Am Chem Soc 133:1428-37. 2011
    ..The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photo-cross-linking...
  32. 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...
  33. 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...
  34. 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...
  35. 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...
  36. 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...
  37. 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...
  38. 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...
  39. 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...
  40. 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...
  41. 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...
  42. 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...
  43. 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...
  44. 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...
  45. 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...
  46. 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
    ....
  47. 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...
  48. 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...