Kirk R Gustafson

Leidos Biomedical Research, Maryland, United States

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Publications (108)292.74 Total impact

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    ABSTRACT: Bioinformatic analysis of data from the NCI-60 cell cytotoxicity screen revealed a subset of extracts that showed selective cytotoxic activity toward human colon carcinoma cell lines. Bioassay-guided fractionation of a colon cancer selective extract from a Philippines collection of the marine sponge Corticium niger provided two new steroidal alkaloids, plakinamines N (1) and O (2), along with two known compounds of the plakinamine class (3, 4). The structures of these compounds were elucidated by interpretation of combined MS and NMR spectroscopic data. Plakinamines N (1), O (2), and J (4) were tested for antiproliferative activity in the NCI-60 screen, and they showed enhanced inhibitory effects against all of the colon cell lines with mean GI50 values of 11.5, 2.4, and 1.4 μM, respectively.
    Journal of natural products. 10/2014;
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    ABSTRACT: Deregulation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR)-70kDa ribosomal protein S6 kinase 1 (p70(S6K)) pathway is commonly observed in many tumors. This pathway controls proliferation, survival, and translation, and its overactivation is associated with poor prognosis for tumor-associated survival. Current efforts focus on the development of novel inhibitors of this pathway. In a cell-based high-throughput screening assay of 15 272 pure natural compounds, we identified pomiferin triacetate as a potent stabilizer of the tumor suppressor programmed cell death 4 (Pdcd4). Mechanistically, pomiferin triacetate appeared as a general inhibitor of the PI3K-Akt-mTOR-p70(S6K) cascade. Interference with this pathway occurred downstream of Akt but upstream of p70(S6K). Specifically, mTOR kinase emerged as the molecular target of pomiferin triacetate, with similar activities against mTOR complexes 1 and 2. In an in vitro mTOR kinase assay pomiferin triacetate dose-dependently inhibited mTOR with an IC50 of 6.2 μM. Molecular docking studies supported the interaction of the inhibitor with the catalytic site of mTOR. Importantly, pomiferin triacetate appeared to be highly selective for mTOR compared to a panel of 17 lipid and 50 protein kinases tested. As a consequence of the mTOR inhibition, pomiferin triacetate efficiently attenuated translation. In summary, pomiferin triacetate emerged as a novel and highly specific mTOR inhibitor with strong translation inhibitory effects. Thus, it might be an interesting lead structure for the development of mTOR- and translation-targeted anti-tumor therapies.
    Biochemical pharmacology 02/2014; · 4.25 Impact Factor
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    ABSTRACT: A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G (1) and netamine M (2). The structures of these tricyclic guanidine alkaloids were established from extensive spectroscopic analyses. Compounds 1 and 2 inhibited cellular degradation of PDCD4 with EC50 values of 1.8 μg/mL and 2.8 μg/mL, respectively. Mirabilin G (1) and netamine M (2) are the first marine natural products reported to stabilize PDCD4 under tumor promoting conditions.
    Marine Drugs 01/2014; 12(8):4593-601. · 3.98 Impact Factor
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    ABSTRACT: Renal or kidney cancer accounts for about 3% of all cancer cases reported each year in the U.S. Molecular signatures that define the cancer, such as the loss of functional VHL, are found in both sporadic and familial cases of cancer. In clear cell renal cancer, the transcription factor HIF-2α has been shown to have a distinct role in tumorigenesis. Our laboratories developed a cell-based screen to identify modulators of HIF-2α. Screening of the NCI's Natural Product Extract Repository resulted in the identification of 10 sponge extracts, from which 12 compounds were isolated. The biological evaluation of these compounds will be discussed including evaluation of HIF-1α vs HIF-2α selectivity and the isolated compounds' effects on mRNA from several pathways regulated by HIF.
    Journal of Natural Products 08/2012; 75(9):1632-6. · 3.29 Impact Factor
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    ABSTRACT: Two new sesterterpenoids named flabelliferins A (1) and B (2) were isolated from the lipophilic extract of the sponge Cateriospongia flabellifera, collected in the South Pacific near Vanuatu. The structure and absolute configuration of these two compounds were assigned by a combination of one- and two-dimensional NMR spectroscopy and by Mosher's ester analysis. Flabelliferin A (1) has a rare 25-homocheilanthane carbon skeleton, while flabelliferin B (2) is a 24-nor-25-homoscalarane sesterterpenoid.
    Journal of Natural Products 07/2012; 75(8):1490-4. · 3.29 Impact Factor
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    ABSTRACT: Loss of the tumor suppressor Pdcd4 was reported for various tumor entities and proposed as a prognostic marker in tumorigenesis. We previously characterized decreased Pdcd4 protein stability in response to mitogenic stimuli, which resulted from p70(S6K1)-dependent protein phosphorylation, β-TrCP1-mediated ubiquitination, and proteasomal destruction. Following high-throughput screening of natural product extract libraries using a luciferase-based reporter assay to monitor phosphorylation-dependent proteasomal degradation of the tumor suppressor Pdcd4, we succeeded in showing that a crude extract from Eriophyllum lanatum stabilized Pdcd4 from TPA-induced degradation. Erioflorin was identified as the active component and inhibited not only degradation of the Pdcd4-luciferase-based reporter but also of endogenous Pdcd4 at low micromolar concentrations. Mechanistically, erioflorin interfered with the interaction between the E3-ubiquitin ligase β-TrCP1 and Pdcd4 in cell culture and in in vitro binding assays, consequently decreasing ubiquitination and degradation of Pdcd4. Interestingly, while erioflorin stabilized additional β-TrCP-targets (such as IκBα and β-catenin), it did not prevent the degradation of targets of other E3-ubiquitin ligases such as p21 (a Skp2-target) and HIF-1α (a pVHL-target), implying selectivity for β-TrCP. Moreover, erioflorin inhibited the tumor-associated activity of known Pdcd4- and IκBα-regulated αtranscription factors, that is, AP-1 and NF-κB, altered cell cycle progression and suppressed proliferation of various cancer cell lines. Our studies succeeded in identifying erioflorin as a novel Pdcd4 stabilizer that inhibits the interaction of Pdcd4 with the E3-ubiquitin ligase β-TrCP1. Inhibition of E3-ligase/target-protein interactions may offer the possibility to target degradation of specific proteins only as compared to general proteasome inhibition.
    PLoS ONE 01/2012; 7(10):e46567. · 3.53 Impact Factor
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    ABSTRACT: Featuring a circular, knotted structure and diverse bioactivities, cyclotides are a fascinating family of peptides that have inspired applications in drug design. Most likely evolved to protect plants against pests and herbivores, cyclotides also exhibit anti-cancer, anti-HIV, and hemolytic activities. In all of these activities, cell membranes appear to play an important role. However, the question of whether the activity of cyclotides depends on the recognition of chiral receptors or is primarily modulated by the lipid-bilayer environment has remained unknown. To determine the importance of lipid membranes on the activity of the prototypic cyclotide, kalata B1, we synthesized its all-D enantiomer and assessed its bioactivities. After the all-D enantiomer had been confirmed by (1)H NMR to be the structural mirror image of the native kalata B1, it was tested for anti-HIV activity, cytotoxicity, and hemolytic properties. The all-D peptide is active in these assays, albeit with less efficiency; this reveals that kalata B1 does not require chiral recognition to be active. The lower activity than the native peptide correlates with a lower affinity for phospholipid bilayers in model membranes. These results exclude a chiral receptor mechanism and support the idea that interaction with phospholipid membranes plays a role in the activity of kalata B1. In addition, studies with mixtures of L and D enantiomers of kalata B1 suggested that biological activity depends on peptide oligomerization at the membrane surface, which determines affinity for membranes by modulating the association-dissociation equilibrium.
    ChemBioChem 09/2011; 12(16):2456-62. · 3.74 Impact Factor
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    ABSTRACT: A high throughput screen for inhibitors of the oncogenic transcription factor activator protein-1 (AP-1) was applied to the NCI repository of natural product extracts. The liphophilic extract of the plant Nothospondias staudtii (Simaroubaceae) displayed significant AP-1 inhibition. Bioassay-guided fractionation of the extract lead to a new quassinoid named nothospondin (1), and the known compound glaucarubinone (2). The structure of 1 was elucidated by spectroscopic methods. Compounds 1 and 2 showed potent, dose-dependent AP-1 inhibition at noncytotoxic concentrations.
    Bioorganic & medicinal chemistry letters 08/2011; 21(15):4397-9. · 2.65 Impact Factor
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    ABSTRACT: A high-throughput cell-based reporter assay designed to identify small-molecule stabilizers of the tumor suppressor Pdcd4 was used to screen extracts in the NCI Natural Products Repository. Bioassay-guided fractionation of an extract from a Papua New Guinea collection of the tropical tree Cryptocarya sp. provided a series of new 5,6-dihydro-α-pyrone-containing 1,3-polyols (1-8), named cryptocaryols A-H. Their structures were assigned from a combination of NMR, MS, and CD studies in conjunction with NMR database comparisons. Compounds 1-8 were found to rescue Pdcd4 from TPA-induced degradation with EC50 concentrations that ranged from 1.3 to 4.9 μM.
    Journal of Natural Products 05/2011; 74(5):1015-20. · 3.29 Impact Factor
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    ABSTRACT: Kidney cancer was the cause of almost 13,000 deaths in the United States in 2009. Loss of function of the VHL tumor suppressor gene (von Hippel-Lindau disease) dramatically increases the risk of developing clear cell kidney cancer. The VHL protein is best understood for its regulation of hypoxia inducible factor (HIF). HIF responds to changes in oxygen levels in the cell and is responsible for mediating the transcriptional response to hypoxia. Of the three known HIFα gene products, HIF-2α appears to play a fundamental role in renal carcinoma. A high throughput screen was developed to identify small molecule inhibitors of HIF-2 gene expression. The screen was performed and yielded 153 confirmed active natural product extracts. Three of the active extracts were from marine soft corals of the order Alcyonacea: Sarcophyton sp., Lobophytum sarcophytoides and Asterospicularia laurae. Bioassay-guided fractionation led to the isolation of two new cembrane diterpenes, (4Z,8S*,9R*,12E,14E)-9-hydroxy-1-(prop-1-en-2-yl)-8,12-dimethyl-oxabicyclo[9.3.2]-hexadeca-4,12,14-trien-18-one (1), and (1E,3E,7R*,8R*,11E)-1-(2-methoxypropan-2-yl)-4,8,12-trimethyloxabicyclo[12.1.0]-pentadeca-1,3,11-triene (7), as well as eight known compounds, 2-6 and 8-10.
    Bioorganic & medicinal chemistry letters 02/2011; 21(7):2113-5. · 2.65 Impact Factor
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    ABSTRACT: Overexpression of ABCG2, a membrane-bound multi-drug transporter, can make tumor cells resistant to treatment with conventional chemotherapeutic agents. A high-throughput screening effort with the NCI repository of natural product extracts revealed that eight tropical plant extracts significantly inhibited the function of ABCG2. This activity was tracked throughout the extract fractionation process to a series of ABCG2 inhibitory flavonoids (1-13). Their structures were identified by a combination of NMR, mass spectrometry, and circular dichroism studies, and this resulted in the elucidation of (2S)-5,7,3'-trihydroxy-4'-methoxy-8-(3''-methylbut-2''-enyl)-flavonone (1), (2S)-5,7,3',5'-tetrahydroxy-8-[3'',8''-dimethylocta-2''(E),7''-dienyl]flavonone (3), and 5,7,3'-trihydroxy-3,5'-dimethoxy-2'-(3'-methylbut-2-enyl)flavone (12) as new compounds.
    Journal of Natural Products 01/2011; 74(2):262-6. · 3.29 Impact Factor
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    ABSTRACT: Enigmazole A (1), a novel phosphate-containing macrolide, was isolated from a Papua New Guinea collection of the marine sponge Cinachyrella enigmatica. The structure of 1, including the absolute stereochemistry at all eight chiral centers, was determined by a combination of spectroscopic analyses and a series of microscale chemical derivatization studies. Compound 1 is comprised of an 18-membered phosphomacrolide that contains an embedded exomethylene-substituted tetrahydropyran ring and an acyclic portion that spans an embedded oxazole moiety. Two additional analogues, 15-O-methylenigmazole A and 13-hydroxy-15-O-methylenigmazole A, were also isolated and assigned. The enigmazoles are the first phosphomacrolides from a marine source and 1 exhibited significant cytotoxicity in the NCI 60-cell line antitumor screen, with a mean GI(50) of 1.7 microM.
    Journal of the American Chemical Society 08/2010; 132(30):10278-85. · 10.68 Impact Factor
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    ABSTRACT: Five new naphthopyrones (1-5) along with the known compounds TMC-256A1, 5,8-dihydroxy-6-methoxy-2-propyl-4H-naphtho[2,3-b]pyran-4-one, TMC-256C1, comaparvin, 6-methoxycomaparvin, and 6-methoxycomaparvin 5-methyl ether (6-11) were isolated from crinoids of the family Comasteridae. All compounds were tested for their ability to inhibit the multidrug transporter ABCG2, which plays a role in drug resistance. Six of the seven angular naphthopyrones showed moderate activity with <60% inhibition of ABCG2-mediated transport as compared to the positive control fumitremorgin C. None of the linear naphthopyrones inhibited ABCG2-mediated efflux.
    Bioorganic & medicinal chemistry letters 07/2010; 20(13):3848-50. · 2.65 Impact Factor
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    ABSTRACT: In previous work, botryllamides discovered from the marine ascidian Botryllus tyreus were characterized as selective inhibitors of the ABCG2 multidrug transporter. However, the structural basis for this activity could not be established. In this study, botryllamide F, the core botryllamide structure, and botryllamide G, the most potent botryllamide ABCG2 inhibitor, were synthesized along with a series of structural variants for evaluation of structure-activity relationships. The biological activity of synthetic botryllamide analogs implied that the 2-methoxy-p-coumaric acid portion, and the degree of double bond conjugation within this group, were critical for inhibition of ABCG2. However, variations in the substituents on the two aryl groups did not appear to significantly impact the potency or degree of inhibition.
    Bioorganic & medicinal chemistry letters 02/2010; 20(4):1330-3. · 2.65 Impact Factor
  • ChemInform 01/2010; 33(43).
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 25(52).
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    ABSTRACT: ABCG2 is a membrane-localized, human transporter protein that has been demonstrated to reduce the intracellular accumulation of substrates through ATP-dependent efflux. Highly expressed in placental syncytiotrophoblasts, brain microvasculature, and the gastrointestinal tract, ABCG2 has been shown to mediate normal tissue protection as well as limit oral bioavailability of substrate compounds. Development of ABCG2 inhibitors for clinical use may allow increased penetration of therapeutic agents into sanctuary sites and increased gastrointestinal absorption. Previously identified inhibitors have lacked potency or specificity or were toxic at concentrations needed to inhibit ABCG2; none are in clinical development. A previously developed high-throughput assay measuring inhibition of ABCG2-mediated pheophorbide a transport was applied to natural product extract libraries. Among the active samples were extracts from the marine ascidian Botryllus tyreus. Bioassay-guided fractionation resulted in purification of a series of botryllamides. Ten botryllamides were obtained, two of which (designated I and J) were novel. Activity against ABCG2 was confirmed by assessing the ability of the compounds to inhibit ABCG2-mediated BODIPY-prazosin transport in ABCG2-transfected HEK293 cells, compete with [(125)I]-iodoarylazidoprazosin (IAAP) labeling of ABCG2, stimulate ABCG2-associated ATPase activity, and reverse ABCG2-mediated resistance.
    ACS Chemical Biology 07/2009; 4(8):637-47. · 5.44 Impact Factor
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    ABSTRACT: NSC 676914 has been identified as a selective nuclear factor-kappaB (NF-kappaB) inhibitor that does not inhibit cell proliferation. This compound was originally identified in a high-throughput cell-based assay for activator protein-1 (AP-1) inhibitors using synthetic compound libraries and the National Cancer Institute natural product repository. NSC 676914 shows activity against NF-kappaB in luciferase reporter assays at concentrations much less than the IC50 for AP-1. A serum response element reporter used as a specificity control and indicator of cell proliferation was relatively insensitive to the compound. Pretreatment with NSC 676914 is here shown to repress 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced IkappaB-alpha phosphorylation and translocation of p65/50 to the nucleus but not the processing of p52 from p100, suggesting the inhibition of NF-kappaB regulator IKKbeta rather than IKKalpha. Inhibition of NF-kappaB activation occurred as a consequence of blocking phosphorylation of IKK. Induction of IkappaB-alpha phosphorylation by TPA was diminished by pretreatment of NSC 676914 even at 1.1 mumol/L. In contrast, kinases c-Jun-NH2-kinase and extracellular signal-regulated kinases 1 and 2, important for AP-1 activation, showed no significant repression by this compound. Furthermore, a Matrigel invasion assay with breast cancer cell lines and a transformation assay in mouse JB6 cells revealed that TPA-induced invasion and transformation responses were completely repressed by this compound. These results suggest that NSC 676914 could be a novel inhibitor having potential therapeutic activity to target NF-kappaB for cancer treatment or prevention.
    Molecular Cancer Therapeutics 04/2009; 8(3):571-81. · 5.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2009; 40(18).

Publication Stats

2k Citations
292.74 Total Impact Points

Institutions

  • 1992–2014
    • Leidos Biomedical Research
      Maryland, United States
  • 1989–2012
    • National Cancer Institute (USA)
      • • Molecular Targets Laboratory
      • • Center for Cancer Research
      • • Developmental Therapeutics Program
      • • Division of Cancer Treatment and Diagnosis
      Maryland, United States
  • 2004–2011
    • University of Queensland 
      • Institute for Molecular Bioscience
      Brisbane, Queensland, Australia
  • 1996–2009
    • NCI-Frederick
      Maryland, United States
  • 2005
    • National Institutes of Health
      • Center for Cancer Research
      Bethesda, MD, United States
  • 2003–2004
    • Wisconsin National Primate Research Center
      Madison, Wisconsin, United States
    • University of California, Santa Cruz
      • Department of Molecular Cell & Developmental Biology
      Santa Cruz, CA, United States