Gregory D Cuny

University of Houston, Houston, Texas, United States

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Publications (110)506.83 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: RIPK1 and RIPK3, two closely related RIPK family members, have emerged as important regulators of pathologic cell death and inflammation. In the current work, we report that the Bcr-Abl inhibitor and anti-leukemia agent ponatinib is also a first-in-class dual inhibitor of RIPK1 and RIPK3. Ponatinib potently inhibited multiple paradigms of RIPK1- and RIPK3-dependent cell death and inflammatory tumor necrosis factor alpha (TNF-α) gene transcription. We further describe design strategies that utilize the ponatinib scaffold to develop two classes of inhibitors (CS and PN series), each with greatly improved selectivity for RIPK1. In particular, we detail the development of PN10, a highly potent and selective "hybrid" RIPK1 inhibitor, capturing the best properties of two different allosteric RIPK1 inhibitors, ponatinib and necrostatin-1. Finally, we show that RIPK1 inhibitors from both classes are powerful blockers of TNF-induced injury in vivo. Altogether, these findings outline promising candidate molecules and design approaches for targeting RIPK1- and RIPK3-driven inflammatory pathologies. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; DOI:10.1016/j.celrep.2015.02.052 · 7.21 Impact Factor
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    ABSTRACT: Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer's disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD. © 2015 Takahashi et al.
    Journal of Experimental Medicine 03/2015; 212(3):319-332. DOI:10.1084/jem.20140413 · 13.91 Impact Factor
  • Angela F Ku, Gregory D Cuny
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    ABSTRACT: 7-Oxygenated aporphines 1-6 possessing anti-configurations have previously been reported. In order to explore their bioactivities, a synthesis was established by utilizing a diastereoselective reductive acid-mediated cyclization followed by palladium-catalyzed ortho-arylations. Moderate XPhos precatalyst loading (10 mol %) and short reaction times (30 min) were sufficient to mediate the arylations. Alkaloids 1-5 were successfully prepared, while (-)-artabonatine A was revised to syn-isomer 30. Consequently, (-)-artabonatine E likely also has a syn-configuration (31).
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    ABSTRACT: Cryptosporidium inosine 5'-monophosphate dehydrogenase (CpIMPDH) has emerged as a therapeutic target for treating Cryptosporidium parasites because it catalyzes a critical step in guanine nucleotide biosynthesis. A 4-oxo-[1]benzopyrano[4,3-c]pyrazole derivative was identified as a moderately potent (IC50 = 1.5 mu M) inhibitor of CpIMPDH. We report a SAR study for this compound series resulting in 8k (IC50 = 20 +/- 4 nM). In addition, an X-ray crystal structure of CpIMPDH IMP 8k is also presented.
    Journal of Medicinal Chemistry 12/2014; 57(24). DOI:10.1021/jm501527z · 5.48 Impact Factor
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    ABSTRACT: Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the pivotal step in guanine nucleotide biosynthesis. IMPDH is a target for immunosuppressive, antiviral, and anticancer drugs, but, as of yet, has not been exploited for antimicrobial therapy. We have previously reported potent inhibitors of IMPDH from the protozoan parasite Cryptosporidium parvum (CpIMPDH). Many pathogenic bacteria, including Bacillus anthracis, Staphylococcus aureus, and Listeria monocytogenes, contain IMPDHs that should also be inhibited by these compounds. Herein, we present the structure-activity relationships for the inhibition of B. anthracis IMPDH (BaIMPDH) and antibacterial activity of 140 compounds from five structurally distinct compound series. Many potent inhibitors of BaIMPDH were identified (78% with IC50 ≤ 1 μM). Four compounds had minimum inhibitory concentrations (MIC) of less than 2 μM against B. anthracis Sterne 770. These compounds also displayed antibacterial activity against S. aureus and L. monocytogenes.
    ACS Medicinal Chemistry Letters 08/2014; 5(8):846-50. DOI:10.1021/ml500203p · 3.07 Impact Factor
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    ABSTRACT: There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-β type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlighted a potent 2-methylpyridine derivative 10 (LDN-214117) with high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for pre-clinical development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG.
    Journal of Medicinal Chemistry 08/2014; 57(19). DOI:10.1021/jm501177w · 5.48 Impact Factor
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    ABSTRACT: STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels.
    PLoS Biology 08/2014; 12(8):e1001923. DOI:10.1371/journal.pbio.1001923 · 11.77 Impact Factor
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    ABSTRACT: PERK is serine/threonine kinase localized to the endoplasmic reticulum (ER) membrane. PERK is activated and contributes to cell survival in response to a variety of physiological stresses that affect protein quality control in the ER, such as hypoxia, glucose depravation, increased lipid biosynthesis, and increased protein translation. Pro-survival functions of PERK are triggered by such stresses, suggesting that development of small-molecule inhibitors of PERK may be efficacious in a variety of disease scenarios. Hence, we have conducted a detailed enzymatic characterization of the PERK kinase to develop a high-throughput-screening assay (HTS) that will permit the identification of small-molecule PERK inhibitors. In addition to establishing the Km of PERK for both its primary substrate, eIF2α, and for adenosine triphosphate, further mechanistic studies revealed that PERK targets its substrate via either a random/steady-state ordered mechanism. For HTS, we developed a time-resolved fluorescence resonance energy transfer-based assay that yielded a robust Z' factor and percent coefficient of variation value, enabling the successful screening of 79,552 compounds. This approach yielded one compound that exhibited good in vitro and cellular activity. These results demonstrate the validity of this screen and represent starting points for drug discovery efforts.
    Journal of Biomolecular Screening 03/2014; 19(7). DOI:10.1177/1087057114525853 · 2.01 Impact Factor
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    ABSTRACT: Glial glutamate transporter EAAT2 plays a major role in glutamate clearance in synaptic clefts. Several lines of evidence indicate that strategies designed to increase EAAT2 expression have potential for preventing excitotoxicity, which contributes to neuronal injury and death in neurodegenerative diseases. We previously discovered several classes of compounds that can increase EAAT2 expression through translational activation. Here, we present efficacy studies of the compound LDN/OSU-0212320, which is a pyridazine derivative from one of our lead series. In a murine model, LDN/OSU-0212320 had good potency, adequate pharmacokinetic properties, no observed toxicity at the doses examined, and low side effect/toxicity potential. Additionally, LDN/OSU-0212320 protected cultured neurons from glutamate-mediated excitotoxic injury and death via EAAT2 activation. Importantly, LDN/OSU-0212320 markedly delayed motor function decline and extended lifespan in an animal model of amyotrophic lateral sclerosis (ALS). We also found that LDN/OSU-0212320 substantially reduced mortality, neuronal death, and spontaneous recurrent seizures in a pilocarpine-induced temporal lobe epilepsy model. Moreover, our study demonstrated that LDN/OSU-0212320 treatment results in activation of PKC and subsequent Y-box-binding protein 1 (YB-1) activation, which regulates activation of EAAT2 translation. Our data indicate that the use of small molecules to enhance EAAT2 translation may be a therapeutic strategy for the treatment of neurodegenerative diseases.
    The Journal of clinical investigation 02/2014; 124(3). DOI:10.1172/JCI66163 · 13.77 Impact Factor
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    ABSTRACT: Cryptosporidium parasites are a major cause of diarrhea and malnutrition in the developing world, a frequent cause of waterborne disease in the developed world and a potential bioterrorism agent. Currently available treatment is limited and Cryptosporidium drug discovery remains largely unsuccessful. As a result, the pharmacokinetic properties required for in vivo efficacy have not been established. We have been engaged in a Cryptosporidium drug discovery program targeting inosine 5' -monophosphate dehydrogenase (CpIMPDH). Here we report the activity of eight potent and selective inhibitors of CpIMPDH in the IL-12 knockout mouse model, which mimics acute human cryptosporidiosis. Two compounds displayed significant antiparasitic activity, validating CpIMPDH as a drug target. The best compound, P131 (250 mg/kg-day), performed equivalently to paromomycin (2000 mg/kg-day) when administered in a single dose, and better than paromomycin when administered in three daily doses. One compound, A110, appeared to promote Cryptosporidium infection. The pharmacokinetic, uptake and permeability properties of the eight compounds were measured. P131 had the lowest systemic distribution, but accumulated to high concentrations within intestinal cells. A110 had the highest systemic distribution. These observations suggest that systemic distribution is not required, and may be a liability, for in vivo antiparasitic activity. Intriguingly, A110 caused specific alterations in fecal microbiota that were not observed with P131 or vehicle alone. Such changes may explain how A110 promotes parasitemia. Collectively, these observations suggest a blueprint for the development of anticryptosporidial therapy.
    Antimicrobial Agents and Chemotherapy 12/2013; 58(3). DOI:10.1128/AAC.02075-13 · 4.45 Impact Factor
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    ABSTRACT: Optimized reaction conditions are established for an intramolecular SRN1 type cyclization of 2-(2-haloarylamino)pyridines (I) to give pyrido[1,2-a]benzimidazoles in good yield.
    ChemInform 11/2013; 44(45):no-no. DOI:10.1002/chin.201345162
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    ABSTRACT: Inhibitor of DNA-binding-1 (ID1) transcription factor is essential for the proliferation and progression of many cancer types including leukemia. However, the ID1 protein has not yet been therapeutically targeted in leukemia. ID1 is normally polyubiquitinated and degraded by the proteasome. Recently, it has been shown that USP1, a ubiquitin specific protease, deubiquitinates ID1 and rescues it from proteasome degradation. Inhibition of USP1 therefore offers a new avenue to target ID1 in cancer. Here, using a Ubiquitin-Rhodamine-based high throughput screening, we identified small molecule inhibitors of USP1 and investigated their therapeutic potential for leukemia. These inhibitors blocked the deubiquitinating enzyme activity of USP1 in vitro in a dose-dependent manner with an IC50 in the high nanomolar range. USP1 inhibitors promoted the degradation of ID1 and, concurrently, inhibited the growth of leukemic cell lines in a dose dependent manner. A known USP1 inhibitor, Pimozide, also promoted ID1 degradation and inhibited growth of leukemic cells. In addition, the growth of primary Acute Myeloid Leukemia (AML) patient-derived leukemic cells was inhibited by a USP1 inhibitor. Collectively, these results indicate that the novel small molecule inhibitors of USP1 promote ID1 degradation and are cytotoxic to leukemic cells. The identification of USP1 inhibitors therefore opens up a new approach for leukemia therapy.
    Molecular Cancer Therapeutics 10/2013; 12(12). DOI:10.1158/1535-7163.MCT-13-0103-T · 6.11 Impact Factor
  • Xiao Wang, Gregory D Cuny, Timothy Noël
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    ABSTRACT: Visible advance: A mild, one-pot Stadler-Ziegler process for CS bond formation has been developed. The method employs the photoredox catalyst [Ru(bpy)3 Cl2 ]⋅6 H2 O irradiated with visible light. A variety of aryl-alkyl and diaryl sulfides were prepared from readily available arylamines and aryl/alkylthiols in good yields. The use of a photo microreactor led to a significant improvement with respect to safety and efficiency.
    Angewandte Chemie International Edition 07/2013; 52(30). DOI:10.1002/anie.201303483 · 11.34 Impact Factor
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    ABSTRACT: Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full-length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA.
    EMBO Molecular Medicine 07/2013; 5(7). DOI:10.1002/emmm.201202305 · 8.25 Impact Factor
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    ABSTRACT: The photo-stimulated cyclization of 2-(2-halophenylamino)pyridines in liquid ammonia afforded pyrido[1,2-a]benzimidazoles via SRN1 mediated C–N bond forming reactions in moderate to excellent yields (58–94%). This general synthetic strategy was also extended to a 2-(2-bromophenylamino)pyrazine to give pyrazino[1,2-a]benzimidazole. Attempts to employ this reaction using N-(2-chlorophenyl)-3-isoquinolinamine, however, resulted in C–C bond formation generating 7H-indolo[2,3-c]isoquinoline.
    ChemInform 07/2013; 69(26):5487–5494. DOI:10.1016/j.tet.2013.04.087
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    ABSTRACT: Although tau accumulation is a feature of several neurodegenerative conditions treatment options for these conditions are non-existent. Targeting tau kinases represents a potential therapeutic approach. Small molecules in the diaminothiazole class are potent tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3xTg-AD and CK-p25. Treatment nearly eliminated sarkosyl-insoluble tau with the most prominent effect on the phosphorylation at Ser404. Treatment also induced the recovery of memory in a fear conditioning assay. Given the contribution of both CDK5/p25 and GSK3β to tau phosphorylation, effective treatment of tauopathies may require dual kinase targeting.
    Journal of Biological Chemistry 06/2013; DOI:10.1074/jbc.M112.436402 · 4.60 Impact Factor
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    ABSTRACT: Cryptosporidium parvum is an enteric protozoan parasite that has emerged as a major cause of diarrhea, malnutrition, and gastroenteritis and poses a potential bioterrorism threat. C. parvum synthesizes guanine nucleotides from host adenosine in a streamlined pathway that relies on inosine 5'-monophosphate dehydrogenase (IMPDH). We have previously identified several parasite-selective C. parvum IMPDH (CpIMPDH) inhibitors by high-throughput screening. In this paper, we report the structure-activity relationship (SAR) for a series of benzoxazole derivatives with many compounds demonstrating CpIMPDH IC50 values in the nanomolar range and >500-fold selectivity over human IMPDH (hIMPDH). Unlike previously reported CpIMPDH inhibitors, these compounds are competitive inhibitors versus NAD(+). The SAR study reveals that pyridine and other small heteroaromatic substituents are required at the 2-position of the benzoxazole for potent inhibitory activity. In addition, several other SAR conclusions are highlighted with regard to the benzoxazole and the amide portion of the inhibitor, including preferred stereochemistry. An X-ray crystal structure of a representative E·IMP·inhibitor complex is also presented. Overall, the secondary amine derivative 15a demonstrated excellent CpIMPDH inhibitory activity (IC50 = 0.5 ± 0.1 nM) and moderate stability (t1/2 = 44 min) in mouse liver microsomes. Compound 73, the racemic version of 15a, also displayed superb antiparasitic activity in a Toxoplasma gondii strain that relies on CpIMPDH (EC50 = 20 ± 20 nM), and selectivity versus a wild-type T. gondii strain (200-fold). No toxicity was observed (LD50 > 50 μM) against a panel of four mammalian cells lines.
    Journal of Medicinal Chemistry 05/2013; DOI:10.1021/jm400241j · 5.48 Impact Factor
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    ABSTRACT: Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-β signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development.
    PLoS ONE 04/2013; 8(4):e62721. DOI:10.1371/journal.pone.0062721 · 3.53 Impact Factor
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    ABSTRACT: The bone morphogenetic protein (BMP) signaling pathway has essential functions in development, homeostasis, and in the normal and pathophysiologic remodeling of tissues. Small molecule inhibitors of the BMP receptor kinase family have been useful for probing physiologic functions of BMP signaling in vitro and in vivo, and may have roles in the treatment of BMP-mediated diseases. Here we describe the development of a selective and potent inhibitor of the BMP type I receptor kinases, LDN-212854, which in contrast to previously described BMP receptor kinase inhibitors exhibits nearly 4 orders of selectivity for BMP versus the closely related TGF-β and Activin type I receptors. In vitro, LDN-212854 exhibits some selectivity for ALK2 in preference to other BMP type I receptors, ALK1 and ALK3, which may permit the interrogation of ALK2-mediated signaling, transcriptional activity and function. LDN-212854 potently inhibits heterotopic ossification in an inducible transgenic mutant ALK2 mouse model of fibrodysplasia ossificans progressiva. These findings represent a significant step towards developing selective inhibitors targeting individual members of the highly homologous BMP type I receptor family. Such inhibitors would provide greater resolution as probes of physiologic function, and improved selectivity against therapeutic targets.
    ACS Chemical Biology 04/2013; 8(6). DOI:10.1021/cb300655w · 5.36 Impact Factor

Publication Stats

3k Citations
506.83 Total Impact Points


  • 2012–2015
    • University of Houston
      • Department of Pharmacological and Pharmaceutical Sciences
      Houston, Texas, United States
    • The Ohio State University
      • Department of Neuroscience
      Columbus, OH, United States
  • 2008–2014
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
    • Tufts University
      • Department of Medicine
      Medford, MA, United States
  • 2007–2014
    • Harvard University
      • Department of Molecular and Cell Biology
      Cambridge, Massachusetts, United States
  • 2013
    • University of California, Santa Barbara
      Santa Barbara, California, United States
    • Idenix Pharmaceuticals, Inc.
      Cambridge, Massachusetts, United States
  • 2003–2013
    • Harvard Medical School
      • • Department of Anesthesia
      • • Department of Microbiology and Immunobiology
      • • Department of Medicine
      • • Department of Cell Biology
      Boston, Massachusetts, United States
  • 2010
    • Massachusetts General Hospital
      • Department of Anesthesia, Critical Care and Pain Medicine
      Boston, Massachusetts, United States