Profile: Greg Cuny

Greg Cuny
Greg Cuny, Ph.D.
Assistant Professor of Medicinal Chemistry
Department of Pharmacological and Pharmaceutical Sciences
549A  Science and Research Building 2
Houston, TX 77204-5037

713-743-1274 (Voice)
713-743-1229 (Fax)
gdcuny@uh.edu

Education

Ph.D. in Organic Chemistry, Massachusetts Institute of Technology, Cambridge, Mass.

B.S. in Chemistry, Grove City College, Grove City, Penn.

Research Interests

The research interest of our lab is in the field of medicinal chemistry. Broadly speaking this encompasses two general areas: 1) synthetic organic chemistry methodology development and application to medicinally interesting natural products; and 2) development of small molecule pharmacological probes.

Currently, we are studying the use of metal-mediated and photo-induced reactions for the construction of several classes of alkaloids. The natural and non-natural products generated are then screened for biological activity in assays related to various therapeutic areas, including oncology. The lab is also involved in several collaborative projects related to pharmacological probe development. One of these projects aims to design selective inhibitors of inosine-5’-monophosphate dehydrogenase (IMPDH) from the protozoan parasites Cryptosporidium parvum and Cryptosporidium hominus, which are potential bio-warfare agents and major causes of diarrhea and malnutrition. This project has also recently expanded to include other microorganisms that may be susceptible to selective IMPDH inhibition.

Another project aims to design subtype selective inhibitors of activin-like kinases (ALKs), such as ALK-1, -2 and -3. These subtypes of ALKs have been implicated in a variety of diseases, including oncology, bone and cardiovascular diseases and anemia of inflammation. Finally, another project aims to design selective inhibitors for kinases implicated in acute and chronic neurodegenerative diseases.

Courses

  • PCOL 6397 Drug Design and Discovery (Spring 2013)

Patents

  • Aquila, B.M.; Bannister, T.D.; Cuny, G.D..; Hauske, J.R.; Holland, J.M; Persons, P.E.; Radeke, H.S.; Wang, F.; Shao, L. Ligand for a monamine receptor and transporters, and methods of use thereof; U.S. 7,816,375, 2010.
  • Aquila, B.M.; Bannister, T.D.; Cuny, G.D.; Hauske, J.R.; Heffernan, M.L.R.; Hoemann, M.Z.; Kessler, D.W.; Shao, L.; Wu, X.; Xie, R.L. Methods for the stereoselective synthesis of substituted piperidines; U.S. 7,692,019, 2010.
  • Aquila, B.M.; Bannister, T.D.; Cuny, G.D.; Hauske, J.R.; Holland, J.M; Persons, P.E.; Radeke, H.S.; Wang, F.; Shao, L. Ligand for a monamine receptor and transporters, and methods of use thereof; U.S. 7,517,892, 2009.
  • Cuny G.D.; Yuan J.; Jagtap P.; Degterev A., Inhibitors of cellular necrosis; U.S. 7,491,743, 2009.
  • Aquila, B.M.; Bannister, T.D.; Cuny, G.D.; Hauske, J.R.; Holland, J.M; Persons, P.E.; Radeke, H.S.; Wang, F.; Shao, L. Method of treating addiction or dependence using a ligand for a monamine receptor or transporter; U.S. 7,294,637, 2007.
  • Aquila, B.M.; Bannister, T.D.; Cuny, G.D.; Hauske, J.R.; Holland, J.M; Persons, P.E.; Radeke, H.S.; Wang, F.; Shao, L. Method of treating addiction or dependence using a ligand for a monamine receptor or transporter; U.S. 7,132,551, 2006.
  • Cuny, G.D.; Shao, L.; Hauske, J.R.; Heffernan, M.L.R.; Aquila, B.M.; Wu, X.; Wang, F.; Bannister, T.D. Heterocyclic analgesic compounds and methods of use thereof; U.S. 7,129,228, 2006.
  • Cuny, G.D.; Hauske, J.R.; Hefferman, M.L.; Holland, J.M.; Persons, P.E.; Radeke, H. Thiazole and other heterocyclic ligands for mammalian dopamine, muscarinic and serotonin receptors and transporters, and
    methods of use thereof; U.S. 7,087,623, 2006.
  • Aquila, B.M.; Bannister, T.D.; Cuny, G.D.; Hauske, J.R.; Heffernan, M.L.R.; Hoemann, M.Z.; Kessler, D.W.; Shao, L.; Wu, X.; Xie, R.L. Methods for the stereoselective synthesis of substituted piperidines; U.S. 7,005,524, 2006.
  • Aquila, B.M.; Cuny, G.D.; Hauske, J.R.; Shao, L.; Wu, X. 3-Substituted piperidines comprising urea functionality, and methods of use thereof; U.S. 6,946,477, 2005.
  • Wu, X.; Aquila, B.M.; Shao, L.; Radeke, H.; Cuny, G.D.; Hauske, J.R.; Xie, R.L. Antipsychotic sulfonamideheterocycles and methods of use thereof; U.S. 6,872,716, 2005.

Selected Publications

Gorla SK, Kavitha M, Zhang M, Chin JE, Liu X, Striepen B, Makowska-Grzyska M, Kim Y, Joachimiak A, Hedstrom L, Cuny GD. Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase. J Med Chem. 2013 May 23;56(10):4028-43. doi: 10.1021/jm400241j. Epub 2013 May 13. PMID: 23668331

Johnson CR, Gorla SK, Kavitha M, Zhang M, Liu X, Striepen B, Mead JR, Cuny GD, Hedstrom L. Phthalazinone inhibitors of inosine-5'-monophosphate dehydrogenase from Cryptosporidium parvum. Bioorg Med Chem Lett. 2013 Feb 15;23(4):1004-7. doi: 10.1016/j.bmcl.2012.12.037. Epub 2012 Dec 27. PMID: 23324406

Gorla SK, Kavitha M, Zhang M, Liu X, Sharling L, Gollapalli DR, Striepen B, Hedstrom L, Cuny GD. Selective and potent urea inhibitors of cryptosporidium parvum inosine 5'-monophosphate dehydrogenase. J Med Chem. 2012 Sep 13;55(17):7759-71. doi: 10.1021/jm3007917. Epub 2012 Sep 5. PMID: 22950983

Hellal, M.; Singh, S.; Cuny, G.D. Synthesis of tetracyclic indoles via intramolecular α-arylation of ketones. J. Org. Chem. 2012, 77, 4123 – 4130.

Kirubakaran, S.; Gorla, S.K.; Sharling, L.; Zhang, M.; Liu, X.; Ray, S.S.; MacPherson, I.S.; Striepen, B.; Hedstrom, L.; Cuny, G.D. Structure-activity relationship study of selective benzimidazole-based inhibitors of Cryptosporidium parvum IMPDH. Bioorg. Med. Chem. Lett. 2012, 22, 1985 – 1988.

Cuny, G.D.; Ulyanova, N.P.; Patnaik, D.; Liu, J.-F.; Lin, X.; Auerbach, K.; Ray, S.S.; Xian, J.; Glicksman, M.A.; Stein, R.L.; Higgins, J.M.G. Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 2015 – 2019.

Hellal, M.; Singh, S.; Cuny, G.D. Monoligated Pd(0)-catalyzed intramolecular ortho- and para-arylation of phenols for the synthesis of aporphine alkaloids.  Synthesis of (-)-lirinine. Tetrahedron 2012, 68, 1674 – 1681.

Laha, J.K.; Cuny, G.D. Synthesis of fused imidazoles, pyrroles and indoles with a defined stereocenter alpha to nitrogen utilizing Mitsunobu alkylation followed by palladium-catalyzed cyclization.  J. Org. Chem. 2011, 8477 – 8482.

Hellal, M.; Cuny, G.D. Microwave assisted copper-free Sonogashira coupling/5-exo-dig cycloisomerization domino reaction: access to 3-(phenylmethylene)isoindolin-1-ones and related heterocycles. Tetrahedron Lett. 2011, 52, 5508 – 5511.

Xing, X.; Chang, L.-C.; Kong, Q.; Colton, C.K.; Lai, L.; Glicksman, M.A.; Li, C.-L.G.; Cuny, G.D. Structureactivity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators. Bioorg. Med. Chem. Lett. 2011, 21, 5774 – 5777.

Laha, J.K.; Barolo, S.M.; Rossi, R.A.; Cuny, G.D. Synthesis of carbolines by photo-stimulated cyclization of anilinohalopyridines. J. Org. Chem. 2011, 76, 6421 – 6425.

Laha, J.K.; Zhang, X.; Qiao, L.; Liu, M.; Chatterjee, S.; Robinson, S.; Kosik, K.S.; Cuny, G.D. Structureactivity relationship study of 2,4-diaminothiazoles as cdk5/p25 kinase inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 2098 - 2101.

Shishova, E.Y.; Stoll, J.M.; Ersoy, B.A.; Shrestha, S.; Scapa, E.F.; Li, Y.; Niepel, M.W.; Su, Y.; Jelicks, L.A.; Stahl, G.L.; Glicksman, M.; Gutierrez-Juarez, R.; Cuny, G.D.; Cohen, D.E. Genetic Ablation or Chemical Inhibition of Phosphatidylcholine Transfer Protein Attenuates Diet-Induced Hepatic Glucose Production Hepatology 2011, 54, 664 – 674.

Steinbicker, A.U.; Sachidanandan, C.; Vonner, A.J.; Yusuf, R.Z.; Deng, D.Y.; Lai, C.S.; Rauwerdink, K.M.; Winn, J.C.; Saez, B.; Cook, C.M.; Szekely, B.A.; Roy, C.N.; Seehra, J.S.; Cuny, G.D.; Scadden, D.T.; Peterson, R.T.; Bloch, K.D.; Yu, P.B. Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood 2011, 117, 4915 – 4923.

Zeng, X.; Sigoillot, F.; Gaur, S.; Choi, S.; Pfaff, K.L.; Oh, D.-C.; Hathaway, N.; Dimova, N.; Cuny, G.D.; King, R.W. Pharmacologic Inhibition of the Anaphase-Promoting Complex Induces A Spindle Checkpoint- Dependent Mitotic Arrest in the Absence of Spindle Damage. Cancer Cell 2010, 18, 382 – 395.

Hellal, M.; Cuny, G.D. Synthesis of the indolizino[7,6-c] quinoline alkaloid isaindigotidione. Org. Lett. 2010, 12, 4628 – 4631.

Cuny, G.D.; Robin, M.; Ulyanova, N.P.; Patnaik, D.; Pique, V.; Casano, G.; Liu, J.-F.; Lin, X.; Xian, J.; Glicksman, M.A.; Stein, R.L.; Higgins, J.M.G. Structure-activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors. Bioorg. Med. Chem. Lett. 2010, 3491 – 3494.

Hellal, M.; Cuny, G.D. Intramolecular aldol reaction of N-acylated (2-aminophenyl)--oxoacetic acids: Rapid access to tri- and tetracyclic 1,2-dihydroquinolin-2(1H)-ones. J. Org. Chem 2010, 75, 3465 – 3468.

Liu, M.; Poulose, S.; Schuman, E.; Zaitsev, A.D.; Dobson, B.; Auerbach, K.; Seyb, K.; Cuny, G.D.; Glicksman, M.A.; Stein, R.L.; Yue, Z. Development of a mechanism-based high-throughput screen assay for leucine-rich repeat kinase 2 – discovery of LRRK2 inhibitors. Anal. Biochem. 2010, 404, 186 – 192.

Leissring, M.A.; Malito, E.; Hedouin, S.; Reinstatler, L.; Sahara, T.; Abdul-Hay, S.O.; Choudhry, S.; Maharvy, G.M.; Fauq, A.H.; Huzarska, M.; May, P.S.; Choi, S.; Logan, T.E.; Turk, B.E.; Cantley, L.C.; Manolopoulou, M.; Tang, W.-J.; Stein, R.L.; Cuny, G.D.; Selkoe, D.J. Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin. PLoS One 2010, 5, e10504.

Nowak, R.J.; Cuny, G.D.; Choi, S.; Lansbury, P.T.; Ray, S.S. Improving binding specificity of pharmacological chaperones that target mutant SOD-1 linked to familial ALS using computational methods. J. Med. Chem. 2010, 53, 2709 – 2718.

Lee, K.; Campbell, J.; Swoboda, J.G.; Cuny, G.D.; Walker, S. Development of improved inhibitors of wall teichoic acid biosynthesis with potent activity against Staphylococcus aureus. Bioorg. Med. Chem. Lett. 2010, 20, 1767 – 1770.

Ouertatani-Sakouhi, H.; Liu, M.; El-Turk, F.; Cuny, G.D.; Glicksman, M.A.; Lashuel, H.A. Kinetic-based highthroughput screening assay to discover novel classes of macrophage migration inhibitory factor inhibitors. J. Biomol. Screen. 2010, 15, 347 – 358.

Colton, C.K.; Kong, Q.; Lai, L.; Zhu, M.X.; Seyb, K.I.; Cuny, G.D.; Xian, J.; Glicksman, M.A.; Lin, C.-L. G. Identification of translational activators of glial glutamate transporter EAAT2 through a cell-based highthroughput screening: An approach for preventing excitotoxicity. J. Biomol. Screen. 2010, 15, 653 - 662.

Cotten, J.F.; Forman, S.A.; Laha, J.K.; Cuny, G.D.; Husain, S.S.; Miller, K.W.; Nguyen, H.H.; Kelly, E.W.; Stewart, D.; Liu, A.; Raines, D.E. Carboetomidate: A pyrrole analogue of etomidate that does not suppress adrenocortical function. Anesthesiology 2010, 112, 637 – 644.

Rosenbaum, D.M; Degterev, A.; David, J; Rosenbaum, P.S.; Roth, S.; Grotta, J.C.; Cuny, G.D.; Yuan, J; Savitz, S.I. Necroptosis, a novel form of caspase-independent cell death, contributes to neuronal damage in a retinal ischemia-reperfusion injury model. J. Neurosci. Res. 2010, 88, 1569 – 1576.

MacPherson, I.S.; Kirubakaran, S.; Gorla, S.K.; Riera, T.V.; D'Aquino, A.J.; Zhang, M.; Cuny, G.D.; Hedstrom, L. The structural basis of Cryptosporidium-specific IMP dehydrogenase inhibitor selectivity. J. Am. Chem. Soc. 2010, 132, 1230 – 1231.

Cuny, G.D. Kinase inhibitors as potential therapeutics for acute and chronic neurodegenerative conditions. Curr. Pharm. Design 2009, 15, 3919 – 3939.

Qiao, L.; Choi, S.; Case, A.; Gainer, T.G.; Seyb, K.; Glicksman, M.A.; Lo, D.C.; Stein, R.L.; Cuny, G.D. Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett. 2009, 6122 – 6126.

Maurya, S.K.; Gollapalli, D.R.; Kirubakaran, S.; Zhang, M.; Johnson, C.R.; Benjamin, N.N.; Hedstrom, L.; Cuny, G.D. Triazole inhibitors of Cryptosporidium parvum inosine 5’-monophosphate dehydrogenase. J. Med. Chem. 2009, 52, 4623 - 4630.

Cabrol, C.; Huzarska, M.; Dinolfo, C.; Rodriguez, M.C.; Reinstatler, L.; Ni, J.; Yeh, L.-A.; Cuny, G.D.; Stein, R.L.; Selkoe, D.J.; Leissring, M.A. Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening. PLoS One 2009, 4, e5274.

Call, M.J.; Xing, X.; Cuny, G.D., Seth, N.P.; Altmann, D.; Fugger, L.; Krogsgaard, M.; Stein, R.L.; Wucherpfennig, K.W. In vivo enhancement of peptide display by MHC class II molecules with small molecule catalysts of peptide exchange. J Immunol. 2009, 182, 6342 – 6352.

Laha, J.K.; Petrou, P.; Cuny, G.D. One-pot synthesis of alpha-carbolines via sequential palladium-catalyzed aryl amination and intramolecular arylation. J. Org. Chem. 2009, 74, 3152 – 3155.

Wu, J.; Xing, X; Cuny, G.D. Synthesis of substituted imidazo[1,5-a]pyrimidines, 1H-pyrrolo[2,3-b]pyridines and 3-methyl-3H-imidazo[4,5-b]pyridines. Lett. Org. Chem. 2009, 6, 203 – 207.

Cuny, G.D. A new class of UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) inhibitors for the treatment of Gram-negative infections: PCT application WO 2008027466. Expert Opin. Ther. Patents 2009, 19, 893 – 899.

Yu, P.B.; Deng, D.Y.; Lai, C.S.; Hong, C.C.; Cuny, G.D.; Bouxsein, M.L.; Peterson, R.T.; Katagiri, T.; Fukuda, T.; Mishina, Y.; Bloch, K.D. BMP type I receptor inhibition reduces heterotopic ossification. Nat. Med. 2008, 14, 1363 – 1369.

Laha, J.K.; Cuny, G.D. Synthesis of tetrazolo[1,5-a]pyridines utilizing trimethylsilyl azide and tetrabutylammonium fluoride hydrate. Synthesis, 2008, 4002 – 4006.

Patnaik, D.; Xian, J.; Glicksman, M.A.; Cuny, G.D.; Stein, R.L.; Higgins, J.M.G. Identification of small molecule inhibitors of the mitotic kinase Haspin by high throughput screening using a homogenous Time- Resolved Fluorescence Resonance Energy Transfer assay. J. Biomol. Screen. 2008, 13, 1025-1034.

Wagle, N.; Xian, J.; Shishova, E.Y.; Wei, J.; Glicksman, M.A.; Cuny, G.D.; Stein, R.L.; Cohen, D.E. Small molecule inhibitors of phosphatidylcholine transfer protein/StarD2 identified by high throughput screening. Anal. Biochem. 2008, 383, 85 – 92.

You, Z.; Savitz, S.I.; Yang, J.; Degterev, A.; Yuan, J.; Cuny, G.D.; Moskowitz, M.A.; Whalen, M.J. Necrostatin-1 reduces histopathology and improves functional outcome after controlled cortical impact in mice. J. Cereb. Blood Flow Metab. 2008, 28, 1564 – 1573.

Cuny, G.D.; Yu, P.B.; Laha, J.K.; Xing, X.; Liu, J.-F.; Lai, C.S.; Deng, D.Y.; Sachidanandan, C.; Bloch, K. D.; Peterson, R. T. Structure activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 4388 – 4392.

Liu, M.; Choi, S.; Cuny, G.D.; Ding, K.; Dobson, B.C.; Glicksman, M.A.; Auerbach, K.; Stein, R.L. Kinetic studies of cdk5/p25 kinase – phosphorylation of tau and complex inhibition by two prototype inhibitors. Biochemistry 2008, 47, 8367 – 8377.

Teng, X.; Keys, H; Yuan, J.; Degterev, A.; Cuny, G.D. Structure activity relationship and liver microsomal stability studies of pyrrole necroptosis inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 3219 – 3223.

Degterev, A.; Hitomi, J.; Germsheid, M.; Ch’en, I.; Korkina, O.; Teng, X.; Abbott, D.; Cuny, G.D.; Yuan, C.; Wagner, G.; Hedrick, S.M.; Gerber, S.A.; Lugovskoy, A.; Yuan, J. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 2008, 4, 313 – 321.

Cuny, G.D.; Degterev, A.; Yuan, J. Necroptosis – A novel cell death mechanism. Drugs Future, 2008, 33, 225–233.

Glicksman, M.A.; Cuny, G.D.; Liu, M.; Dobson, B.; Auerbach, K.; Stein, R.L.; Kosik, K.S. New approaches to the discovery of cdk5 inhibitors. Curr. Alzheimer Res. 2007, 4, 547 – 549.

Teng, X.; Keys, H.; Jeevanandam, A.; Porco, J.A., Jr.; Degterev, A.; Yuan, J.; Cuny, G.D. Structure activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 6836 – 6840.

Mermerian, A.H.; Case, A.; Stein, R.L.; Cuny, G.D. Structure-activity relationship, kinetic mechanism and selectivity for a new class of ubiquitin C-terminal hydrolase-L1 (UCH-L1) inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 3729 – 3732.

Jagtap, P. G.; Degterev, A.; Choi, S.; Keys, H.; Yuan, J.; Cuny, G.D. Structure activity relationship study of tricyclic necroptosis inhibitors. J. Med. Chem. 2007, 50, 1886 – 1895.

Barolo, S.M.; Teng, X.; Cuny, G.D.; Rossi, R.A. Syntheses of aporphine and homoaporphine alkaloids by intramolecular ortho-arylation of phenols with aryl halides via SRN1 reations in liquid ammonia. J. Org. Chem. 2006, 71, 8493 – 8499.

Tucker, S.; Ahl, M.; Cho, H.-H.; Bandyopadhyay, S.; Cuny, G.D.; Bush, A.I.; Goldstein, L.E.; Westaway, D.; Huang, X.; Rogers, J.T. RNA therapeutics directed to the non coding regions of APP mRNA, in vivo antiamyloid efficacy of paroxetine, erythromycin and N-acetyl cysteine. Curr. Alzheimer Res. 2006, 3, 221 – 227.

Nicholson, M.J.; Moradi, B.; Seth, N.P.; Xing, X.; Cuny, G.D.; Stein, R.L.; Wucherpfennig, K.W. Small molecules that enhance the catalytic efficiency of HLA-DM. J Immunol. 2006, 176, 4208 – 4220.

Zhang, D.; Xing, X. Cuny, G.D. Synthesis of hydantoins from enantiomerically pure alpha-amino amides without epimerization. J. Org. Chem. 2006, 71, 1750 – 1753.

Cuny, G.D.; Lee, K.; Choi, S. Utilization of a tandem Michael-Dieckmann reaction to synthesize orixalone A. Lett. Org. Chem. 2006, 3, 68 – 72.

Research Grants and Contracts 

R01 AI093459; IMPDH-Targeted antibiotics for select agents; Hedstrom (PI); 6/1/11–5/30/16; NIH; Role: Co-investigator.

Memberships

  • American Chemical Society

Editorial Appointments & Professional Service

  • Journal Reviewer (ad hoc): ACS Medicinal Chemistry Letters, Bioorganic and Medicinal Chemistry Letters, European Journal of Medicinal Chemistry, Journal of Organic Chemistry, Journal of the American Chemical Society, Journal of Natural Products, Tetrahedron, Tetrahedron Letters, Organic Letters, Synlett, Molecular Diversity and Nature Chemical Biology.