Gregory R J Thatcher

University of Illinois at Chicago, Chicago, Illinois, United States

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Publications (127)517.03 Total impact

  • Marton Siklos · Manel BenAissa · Gregory R.J. Thatcher
  • Cancer Research 08/2015; 75(15 Supplement):4497-4497. DOI:10.1158/1538-7445.AM2015-4497 · 9.33 Impact Factor
  • European Journal of Cancer 11/2014; 50:103. DOI:10.1016/S0959-8049(14)70442-3 · 5.42 Impact Factor
  • Hitisha Patel · Rui Xiong · Jiong Zhao · Mary Ellen Molloy · Debra Tonetti · Gregory R.J Thatcher
    Cancer Research 10/2014; 74(19 Supplement):2710-2710. DOI:10.1158/1538-7445.AM2014-2710 · 9.33 Impact Factor
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    ABSTRACT: Previous data demonstrate that Bexarotene (Bex), an RXR agonist, reduces soluble and insoluble amyloid-β (Aβ) in Alzheimer's disease (AD)-transgenic (Tg) mice either via increasing the levels of mouse apolipoprotein E (apoE) or increasing ABCA1/ABCG1-induced apoE lipoprotein-association/lipidation. However, while the mechanism of action of RXR agonists remains unclear, a major concern for their use is human (h)-APOE4, the greatest AD genetic-risk factor. If APOE4 imparts a toxic gain-of-function, then increasing apoE4 may increase soluble Aβ, likely the proximal AD neurotoxin. If APOE4 imparts a loss-of-function, then ABCA1/ABCG1-induced lipidation of apoE4 may be beneficial. In novel EFAD-Tg mice (overexpressing h-Aβ42 with h-APOE), levels of soluble Aβ (Aβ42 and oligomeric Aβ (oAβ)) are highest in E4FAD-hippocampus (HP) > E3FAD-HP > E4FAD-cortex (CX) > E3FAD-CX, while levels of lipoprotein-associated/lipidated apoE have the opposite pattern (6-months, M). In E4FAD-HP, short-term RXR agonist treatment (Bex or LG100268; 5.75-6M) increased ABCA1, apoE4 lipoprotein-association/lipidation and apoE4/Aβ complex, decreased soluble Aβ and increased PSD95. In addition, hydrogel delivery, which mimics low sustained release, was equally effective as gavage for Bex and LG in lowering soluble Aβ with APOE4. RXR agonists induced no beneficial effects in the E4FAD-HP in a prevention protocol (5-6M), and increased soluble Aβ levels in E3FAD-CX and E4FAD-CX (5.75-6M), likely the result of systemic hepatomegaly. Thus, RXR agonists address the loss-of-function associated with APOE4 and exacerbated by Aβ pathology--low levels of apoE4 lipoprotein-association/lipidation. Further studies are vital to address whether RXR agonists are an APOE4-specific AD therapeutic and the systemic side effects that limit translational application.
    Journal of Biological Chemistry 09/2014; 289(44). DOI:10.1074/jbc.M114.600833 · 4.57 Impact Factor
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    ABSTRACT: Endocrine-resistant breast cancer is a major clinical obstacle. The use of 17beta-estradiol (E2) has re-emerged as a potential treatment option following exhaustive use of tamoxifen (TAM) or aromatase inhibitors although side effects have hindered its clinical usage. Protein kinase C alpha (PKCalpha) expression was shown to be a predictor of disease outcome for patients receiving endocrine therapy and may predict a positive response to an estrogenic treatment. Here, we have investigated the use of novel benzothiophene selective estrogen mimics (SEMs) as an alternative to E2 for the treatment of TAM-resistant breast cancer. Following in vitro characterization of SEMs, a panel of clinically relevant PKCalpha-expressing, TAM-resistant models were used to investigate the antitumor effects of these compounds. SEM treatment resulted in growth inhibition and apoptosis of TAM-resistant cell lines in vitro. In vivo SEM treatment induced tumor regression of TAM-resistant T47D:A18/PKCalpha and T47D:A18-TAM1 tumor models. T47D:A18/PKCalpha tumor regression was accompanied by translocation of ERalpha to extranuclear sites, possibly defining a mechanism through which these SEMs initiate tumor regression. SEM treatment did not stimulate growth of E2-dependent T47D:A18/neo tumors. Additionally, unlike E2 or TAM, treatment with SEMs did not stimulate uterine weight gain. These findings suggest the further development of SEMs as a feasible therapeutic strategy for the treatment of endocrine-resistant breast cancer without the side effects associated with E2.
    Molecular Cancer Therapeutics 09/2014; 13(11). DOI:10.1158/1535-7163.MCT-14-0319 · 5.68 Impact Factor
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    Kevin Koster · Mary Jo LaDu · Jia Luo · Gregory Thatcher · Leon Tai
    Alzheimer's and Dementia 07/2014; 10(4):P920-P921. DOI:10.1016/j.jalz.2014.07.130 · 12.41 Impact Factor
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    ABSTRACT: The risk of developing hormone-dependent cancers with long-term exposure to estrogens is attributed both to proliferative, hormonal actions at the estrogen receptor (ER), and chemical carcinogenesis elicited by genotoxic, oxidative estrogen metabolites. Non-tumorigenic MCF-10A human breast epithelial cells are classified as ER(-) and undergo estrogen-induced malignant transformation. Selective estrogen receptor modulators (SERMs), in use for breast cancer chemoprevention and for post-menopausal osteoporosis, were observed to inhibit malignant transformation, as measured by anchorage-independent colony growth. This chemopreventive activity was observed to correlate with reduced levels of oxidative estrogen metabolites, cellular ROS, and DNA oxidation. The ability of raloxifene, desmethylarzoxifene (DMA), and bazedoxifene to inhibit this chemical carcinogenesis pathway was not shared by 4-hydroxytamoxifen. Regulation of Phase 2 rather than Phase 1 metabolic enzymes was implicated mechanistically: raloxifene and DMA were observed to upregulate sulfotransferase (SULT 1E1) and glucuronidase (UGT 1A1). The results support upregulation of Phase 2 metabolism in detoxification of catechol estrogen metabolites leading to attenuated ROS formation as a mechanism for inhibition of malignant transformation by a subset of clinically important SERMs.
    Cancer Prevention Research 03/2014; 7(5). DOI:10.1158/1940-6207.CAPR-13-0296 · 4.44 Impact Factor
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    ABSTRACT: Breast cancer remains a significant cause of death in women, and few therapeutic options exist for estrogen receptor negative (ER (-)) cancers. Epigenetic reactivation of target genes using histone deacetylase (HDAC) inhibitors has been proposed in ER (-) cancers to resensitize to therapy using selective estrogen receptor modulators (SERMs) that are effective in ER (+) cancer treatment. Based upon preliminary studies in ER (+) and ER (-) breast cancer cells treated with combinations of HDAC inhibitors and SERMs, hybrid drugs, termed SERMostats, were designed with computational guidance. Assay for inhibition of four type I HDAC isoforms and antagonism of estrogenic activity in two cell lines yielded a SERMostat with 1-3 μM potency across all targets. The superior hybrid caused significant cell death in ER (-) human breast cancer cells and elicited cell death at the same concentration as the parent SERM in combination treatment and at an earlier time point.
    ChemMedChem 03/2014; 9(3). DOI:10.1002/cmdc.201300270 · 2.97 Impact Factor
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    ABSTRACT: The front cover picture shows a novel hybrid SERMostat that acts as both a class I histone deacetylase (HDAC) inhibitor and a selective estrogen receptor modulator (SERM). A combinatorial therapy using an HDAC inhibitor and antiestrogen drug is currently being tested in clinical trials for the treatment of ER() breast cancer, since HDAC inhibitors are proposed to increase transcription of ER (blue arrow). Based on this concept, SERMostats were designed with computational guidance and evaluated for their activity against ER() breast cancer cells. The SERMostats showed increased efficacy compared with the combinatorial treatment using the parent SERM and HDAC inhibitor. For further details, see the Full Paper by Gregory R. J. Thatcher et al. on p. 602 ff.
    ChemMedChem 03/2014; 9(3):413-413. DOI:10.1002/cmdc.201490005 · 2.97 Impact Factor
  • Adrian C. Nicolescu · Gregory R. J. Thatcher
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    ABSTRACT: Classic organic nitrates, such as nitroglycerin (GTN), are important vasodilators classed as NO donors, since biological activity is assumed to result entirely from bioactivation to NO and activation of soluble guanylate cyclase (sGC). Para-substituted aryl disulfanyl nitrate esters (SS-nitrates), designed based on a sulfhydryl-dependent mechanism of NO release, were investigated for their sGC activation. To obtain further insights into their interaction with hemoproteins, SS-nitrates were reacted with oxyhemoglobin (O2-Hb). SS-nitrates activated sGC with higher efficacy than GTN in the presence of cysteine. Some SS-nitrates, unlike GTN, activated sGC in the absence of cysteine. Linear correlations between the σp Hammett parameters and sGC activation efficacies or rates of O2-Hb oxidation by SS-nitrates in the presence of cysteine were found. Our results validate the design of SS-nitrates to circumvent the need for cysteine-mediated bioactivation and hint at NO-dependent and NO-independent mechanisms of sGC activation.
    Medicinal Chemistry Communication 01/2014; 5(1):51. DOI:10.1039/c3md00261f · 2.50 Impact Factor
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    ABSTRACT: Chlormethiazole (CMZ), a clinical sedative/anxiolytic agent, did not reach clinical efficacy in stroke trials despite neuroprotection demonstrated in numerous animal models. Using CMZ as a lead compound, neuroprotective methiazole (MZ) analogues were developed, and neuroprotection and GABAA receptor dependence were studied. Eight MZs were selected from a novel library, of which two were studied in detail. Neuroprotection, glutamate release, intracellular calcium and response to GABA blockade by picrotoxin were measured in rat primary cortical cultures using four cellular models of neurodegeneration. GABA potentiation was assayed in oocytes expressing the α1 β2 γ2 GABAA receptor. Neuroprotection against a range of insults was retained even with substantial chemical modification. Dependence on GABAA receptor activity was variable: at the extremes, neuroprotection by GN-28 was universally sensitive to picrotoxin, while GN-38 was largely insensitive. In parallel, effects on extracellular glutamate and intracellular calcium were associated with GABAA dependence. Consistent with these findings, GN-28 potentiated α1 β2 γ2 GABAA function, whereas GN-38 had weakly inhibitory effect. Neuroprotection against moderate dose oligomeric Aβ1-42 was also tolerant to structural changes. The results support the concept that CMZ does not contain a single pharmacophore, rather that broad-spectrum neuroprotection results from a GABAA -dependent mechanism represented by GN-28, combined with a mechanism represented in GN-38 that shows the least dependence on GABAA receptors. These findings allow further refinement of the neuroprotective pharmacophore and investigation into secondary mechanisms that will assist in identifying methiazole-based compounds of use in treating neurodegeneration.
    British Journal of Pharmacology 10/2013; 171(2). DOI:10.1111/bph.12454 · 4.84 Impact Factor
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    ABSTRACT: SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) ARE EFFECTIVE THERAPEUTICS THAT PRESERVE FAVORABLE ACTIONS OF ESTROGENS ON BONE AND ACT AS ANTIESTROGENS IN BREAST TISSUE, DECREASING THE RISK OF VERTEBRAL FRACTURES AND BREAST CANCER, BUT THEIR POTENTIAL IN NEUROPROTECTIVE AND PROCOGNITIVE THERAPY IS LIMITED BY: 1) an increased lifetime risk of thrombotic events; and 2) an attenuated response to estrogens with age, sometimes linked to endothelial nitric oxide synthase (eNOS) dysfunction. Herein, three 3(rd) generation SERMs with similar high affinity for estrogen receptors (ERα, ERβ) were studied: desmethylarzoxifene (DMA), FDMA, and a novel NO-donating SERM (NO-DMA). Neuroprotection was studied in primary rat neurons exposed to oxygen glucose deprivation; reversal of cholinergic cognitive deficit was studied in mice in a behavioral model of memory; long term potentiation (LTP), underlying cognition, was measured in hippocampal slices from older 3×Tg Alzheimer's transgenic mice; vasodilation was measured in rat aortic strips; and anticoagulant activity was compared. Pharmacologic blockade of GPR30 and NOS; denudation of endothelium; measurement of NO; and genetic knockout of eNOS were used to probe mechanism. Comparison of the three chemical probes indicates key roles for GPR30 and eNOS in mediating therapeutic activity. Procognitive, vasodilator and anticoagulant activities of DMA were found to be eNOS dependent, while neuroprotection and restoration of LTP were both shown to be dependent upon GPR30, a G-protein coupled receptor mediating estrogenic function. Finally, the observation that an NO-SERM shows enhanced vasodilation and anticoagulant activity, while retaining the positive attributes of SERMs even in the presence of NOS dysfunction, indicates a potential therapeutic approach without the increased risk of thrombotic events.
    PLoS ONE 08/2013; 8(8):e70740. DOI:10.1371/journal.pone.0070740 · 3.23 Impact Factor
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    ABSTRACT: The promising therapeutic potential of the NO-donating hybrid aspirin prodrugs (NO-ASA) includes induction of chemopreventive mechanisms and has been reported in almost 100 publications. One example, NCX-4040 (pNO-ASA), is bioactivated by esterase to a quinone methide (QM) electrophile. In cell cultures, pNO-ASA and QM-donating X-ASA prodrugs that cannot release NO rapidly depleted intracellular GSH and caused DNA damage; however, induction of Nrf2 signaling elicited cellular defense mechanisms including upregulation of NAD(P)H:quinone oxidoreductase-1 (NQO1) and glutamate-cysteine ligase (GCL). In HepG2 cells, the "NO-specific" 4,5-diaminofluorescein reporter, DAF-DA, responded to NO-ASA and X-ASA, with QM-induced oxidative stress masquerading as NO. LC-MS/MS analysis demonstrated efficient alkylation of Cys residues of proteins including glutathione-S-transferase-P1 (GST-P1) and Kelch-like ECH-associated protein 1 (Keap1). Evidence was obtained for alkylation of Keap1 Cys residues associated with Nrf2 translocation to the nucleus, nuclear translocation of Nrf2, activation of antioxidant response element (ARE), and upregulation of cytoprotective target genes. At least in cell culture, pNO-ASA acts as a QM donor, bioactivated by cellular esterase activity to release salicylates, NO(3)(-), and an electrophilic QM. Finally, two novel aspirin prodrugs were synthesized, both potent activators of ARE, designed to release only the QM and salicylates on bioactivation. Current interest in electrophilic drugs acting via Nrf2 signaling suggests that QM-donating hybrid drugs can be designed as informative chemical probes in drug discovery.
    Chemical Research in Toxicology 10/2012; 25(12). DOI:10.1021/tx3003609 · 3.53 Impact Factor
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    ABSTRACT: Learning and memory deficits in Alzheimer's disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described that uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (MZ) derivatives were synthesized, based upon a lead neuroprotective pharmacophore acting in part by GABA(A) receptor potentiation. MZ derivatives were assayed for protection of primary neurons against oxygen-glucose deprivation and excitotoxicity. Selected neuroprotective derivatives were incorporated into NO-chimera prodrugs, coined nomethiazoles. To provide proof of concept for the nomethiazole drug class, selected examples were assayed for restoration of synaptic function in hippocampal slices from AD-transgenic mice, reversal of cognitive deficits, and brain bioavailability of the prodrug and its neuroprotective MZ metabolite. Taken together, the assay data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD.
    Journal of Medicinal Chemistry 07/2012; 55(15):6784-801. DOI:10.1021/jm300353r · 5.45 Impact Factor
  • Jia Luo · Lawren VandeVrede · Zhihui Qin · Ehsan Tavasolli · Gregory Thatcher
    Alzheimer's and Dementia 07/2012; 8(4):P244. DOI:10.1016/j.jalz.2012.05.653 · 12.41 Impact Factor
  • Irida Kastrati · Vladislav A. Litosh · Gregory R.J. Thatcher · Jonna Frasor
    Cancer Research 06/2012; 72(8 Supplement):3732-3732. DOI:10.1158/1538-7445.AM2012-3732 · 9.33 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):LB-64-LB-64. DOI:10.1158/1538-7445.AM2012-LB-64 · 9.33 Impact Factor
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    ABSTRACT: The bioactivation of both endogenous and equine estrogens to electrophilic quinoid metabolites has been postulated as a contributing factor in carcinogenic initiation and/or promotion in hormone sensitive tissues. Bearing structural resemblance to estrogens, extensive studies have shown that many selective estrogen receptor modulators (SERMs) are subject to similar bioactivation pathways. Lasofoxifene (LAS), a third generation SERM which has completed phase III clinical trials for the prevention and treatment of osteoporosis, is currently approved in the European Union for this indication. Previously, Prakash et al. (Drug Metab. Dispos. (2008) 36, 1218-1226) reported that similar to estradiol, two catechol regioisomers of LAS are formed as primary oxidative metabolites, accounting for roughly half of the total LAS metabolism. However, the potential for further oxidation of these catechols to electrophilic o-quinones has not been reported. In the present study, LAS was synthesized and its oxidative metabolism investigated in vitro under various conditions. Incubation of LAS with tyrosinase, human liver microsomes, or rat liver microsomes in the presence of GSH as a trapping reagent resulted in the formation of two mono-GSH and two di-GSH catechol conjugates which were characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Similar conjugates were also detected in incubations with P450 3A4, P450 2D6, and P450 1B1 supersomes. Interestingly, these conjugates were also detected as major metabolites when compared to competing detoxification pathways such as glucuronidation and methylation. The 7-hydroxylasofoxifene (7-OHLAS) catechol regioisomer was also synthesized and oxidized either chemically or enzymatically to an o-quinone that was shown to form depurinating adducts with DNA. Collectively, these data show that analogous to estrogens, LAS is oxidized to catechols and o-quinones which could potentially contribute to in vivo toxicity for this SERM.
    Chemical Research in Toxicology 05/2012; 25(7):1472-83. DOI:10.1021/tx300142h · 3.53 Impact Factor
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    Isaac T Schiefer · Lawren VandeVrede · Mauro Fa · Ottavio Arancio · Gregory R J Thatcher
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    ABSTRACT: Furoxans (1,2,5-oxadiazole-N-oxides) are thiol-bioactivated NO-mimetics that have not hitherto been studied in the CNS. Incorporation of varied substituents adjacent to the furoxan ring system led to modulation of reactivity toward bioactivation, studied by HPLC-MS/MS analysis of reaction products. Attenuated reactivity unmasked the cytoprotective actions of NO in contrast to the cytotoxic actions of higher NO fluxes reported previously for furoxans. Neuroprotection was observed in primary neuronal cell cultures following oxygen glucose deprivation (OGD). Neuroprotective activity was observed to correlate with thiol-dependent bioactivation to produce NO(2)(-), but not with depletion of free thiol itself. Neuroprotection was abrogated upon cotreatment with a sGC inhibitor, ODQ, thus supporting activation of the NO/sGC/CREB signaling cascade by furoxans. Long-term potentiation (LTP), essential for learning and memory, has been shown to be potentiated by NO signaling, therefore, a peptidomimetic furoxan was tested in hippocampal slices treated with oligomeric amyloid-β peptide (Aβ) and was shown to restore synaptic function. The novel observation of furoxan activity of potential therapeutic use in the CNS warrants further studies.
    Journal of Medicinal Chemistry 03/2012; 55(7):3076-87. DOI:10.1021/jm201504s · 5.45 Impact Factor

Publication Stats

2k Citations
517.03 Total Impact Points


  • 2003–2014
    • University of Illinois at Chicago
      • • Department of Medicinal Chemistry and Pharmacognosy
      • • College of Pharmacy
      Chicago, Illinois, United States
  • 1991–2010
    • Queen's University
      • • Department of Chemistry
      • • Department of Pharmacology and Toxicology
      Kingston, Ontario, Canada
  • 2009
    • University of Chicago
      Chicago, Illinois, United States
  • 1996–1997
    • Queens University of Charlotte
      • Chemistry
      New York, United States