John O. Trent, Ph.D.

John O. Trent, Ph.D.

Education:

B.Sc.(hons), First Class, Chemistry, University of Canterbury, New Zealand 1987
Ph.D., Chemistry, University of Canterbury, New Zealand 1992
Postdoctoral Fellowship, Department of Organic Chemistry, University of Geneva, Switzerland 1994
Postdoctoral Fellowship, CRC Biomolecular Structure Unit, The Institute of Cancer Research, Sutton, Surrey, U.K 1996

Curriculum Vitae

Current Positions:

Deputy Director of Basic and Translational Research, James Graham Brown Cancer Center
Experimental Therapeutics Program Leader, James Graham Brown Cancer Center
Professor of Medicine, and Biochemistry and Molecular Biology
Wendell Cherry Endowed Chair in Cancer Translational Research
Director, Kosair Charities Pediatric Oncology Research Program
Director, James Graham Brown Cancer Center Molecular Modeling Facility

Contact Information:

Clinical Translational Research Building, Room 224
University of Louisville
505 Hancock St.
Louisville, KY 40202, USA
Phone 502-852-2194
Fax 502-852-7979
Email: john.trent@louisville.edu

Research Description

The Trent Laboratory is primarily interested in DNA and protein structure, computational biology, biophysics, drug discovery and design. We take an interdisciplinary computational and experimental approach to understand the structure and biomolecular interactions of a molecular target and then target it with small molecules. We have had a long-standing interest in DNA as a target (including duplex, triplex, and particularly quadruplex DNA). We have discovered and initially developed, in collaboration with Drs. Paula Bates and Donald Miller, AS1411, the first anticancer aptamer to progress through Phase II cancer clinical trials. Our recent efforts in this area are towards targeting the biologically relevant quadruplex regions of the human telomere and oncogene promoters in collaboration with Dr. Brad Chaires.

We also are heavily involved in the discovery of new therapeutics against protein targets, such as CCR5, CXCR4, nucleolin, 6-phosphofructo-2-kinase, choline kinase, Bcl-2, and macrophage inhibitory factor, amongst many others. Our collaboration with Dr. Jason Chesney on 6-phosphofructo-2-kinase has led to our second drug to go from discovery to clinical trials (May 2014).

We have developed protocols and resources, in conjunction with the Modeling Core Facility, that routinely can computationally screen tens of millions of compounds against any particular target of interest using virtual screening for drug discovery.

Representative Publications:

Drug Discovery

Chesney J, Clark J, Lanceta L, Trent JO, Telang S.  Targeting the sugar metabolism of tumors with a first-in-class 6-phosphofructo-2-kinase (PFKFB4) inhibitor.  Oncotarget 2015 Jul 20;6(20):18001-11. PMID 26221874.

Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A, Rasku MA, Arumugam S, Dean WL, Eaton J, Lane A, Trent JO, Chesney J. .Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth.  Molecular Cancer Therapy 2008 Jan;7(1):110-20. PMID: 18202014.

Winner M, Meier J, Zierow S, Rendon BE, Crichlow GV, Riggs R, Bucala R, Leng L, Smith N, Lolis E, Trent JO, Mitchell RA.  A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells.  Cancer Research 2008 Sep 15;68(18):7253-7. PMID: 18794110. PMCID: PMC2726006.

Clem BF, Clem AL, Yalcin A, Goswami U, Arumugam S, Telang S, Trent JO, Chesney J.  A novel small molecule antagonist of choline kinase-α that simultaneously suppresses MAPK and PI3K/AKT signaling.  Oncogene 2011 Jul 28;30(30):3370-80. Epub 2011 Mar 21. PMID: 21423211. PMCID: PMC3136659.

The Structure of Human Telomere Quadruplex DNA

Sun D, Thompson B, Cathers BE, Salaza, M, Kerwin SM, Trent JO, Jenkins TC, Neidle S, Hurley LH.  Inhibition of human telomerase by a G-quadraplex-interactive compound.  Journal of Medicinal Chemistry 1997;40:2113-6. PMID: 9216827.

Li J, Correia JJ, Wang L, Trent JO, Chaires JB.  Not so crystal clear: the structure of the human telomere G-quadruplex in solution differs from that present in a crystal.  Nucleic Acids Research 2005 Aug 16;33(14):4649-59. PMID: 16106044.

Miller MC, Buscaglia R, Chaires JB, Lane AN, Trent JO.  Hydration is a major determinant of the G-quadruplex stability and conformation of the human telomere 3' sequence of d(AG(3)(TTAG(3))(3)).  Journal of the American Chemical Society 2010 Dec 8;132(48):17105-8. Epub 2010 Nov 18.  PMID: 21087016.

Le HT, Dean WL, Buscaglia R, Chaires JB, Trent JO.  An investigation of G-quadruplex structural polymorphism in the human telomere using a combined approach of hydrodynamic bead modeling and molecular dynamics simulation.  Journal of Physical Chemistry B 2014 May 22;118(20):5390-405. Epub 2014 Apr 29. PMID: 24779348. PMCID: PMC4032189.

Resolution Of Quaduplex Structural Polymorphism

Dailey MM, Miller MC, Bates PJ, Lane AN, Trent JO.  Resolution and characterization of the structural polymorphism of a single quadruplex-forming sequence.  Nucleic Acids Research 2010 Aug;38(14):4877-88. Epub 2010 Mar 25. PMID:20348136. PMCID: PMC2919704.

Le HT, Miller MC, Buscaglia R, Dean WL, Holt PA, Chaires JB, Trent JO.  Not all G-quadruplexes are created equally: an investigation of the structural polymorphism of the c-Myc G-quadruplex-forming sequence and its interaction with the porphyrin TMPyP4.  Organic & Biomolecular Chemistry 2012 Dec 21;10(47):9393-404. doi: 10.1039/c2ob26504d. Epub 2012 Oct 29. PMID: 23108607. PMCID: PMC3501587.

Miller MC, Le HT, Dean WL, Holt PA, Chaires JB, Trent JO.  Polymorphism and resolution of oncogene promoter quadruplex-forming sequences.  Organic & Biomolecular Chemistry 2011 Oct 26;9(22):7633-7. Epub 2011 Sep 21. PMID: 21938285. PMCID: PMC3962748.

Chaires JB, Trent JO, Gray RD, Dean WL, Buscaglia R, Thomas SD, Miller DM.  An improved Model for the hTERT Promoter Quadruplex. PLoS One. 2014 Dec 19;9(12):e115580. doi: 10.1371/journal.pone.0115580. eCollection 2014. PMID: 25526084. PMCID: PMC4272262.

First In Class Anticancer Aptamer, AS1411

Bates PJ, Kahlon J, Thomas SD, Trent JO, Miller DM.  Antiproliferative activity of G-rich oligonucleotides correlates with protein binding.  Journal of Biological Chemistry 1999 Sep 10;274(37):26369-77. PMID: 10473594. [ http://www.jbc.org/content/274/37/26369.long ]

Bates PJ, Laber DA, Miller DM, Thomas SD, Trent JO.  Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer.  Experimental & Molecular Pathology 2009 Jun;86(3):151-64. Epub 2009 Jan 20. PMID: 19454272. PMCID: PMC2716701.

Xu X, Hamhouyia F, Thomas SD, Burke TJ, Girvan AC, McGregor WG, Trent JO, Miller DM, Bates PJ.  Inhibition of DNA replication and induction of S phase cell cycle arrest by G-rich oligonucleotides.  Journal of Biological Chemistry 2001 Nov 16;276(46):43221-30. PMID: 11555643. [ http://www.jbc.org/content/276/46/43221.long ]

Li J, Zheng H, Bates PJ, Malik T, Li XF, Trent JO, Ng CK.  Aptamer imaging with Cu-64 labeled AS1411: Preliminary assessment in lung cancer.  Nuclear Medicine & Biology 2014 Feb;41(2):179-85. doi: 10.1016/j.nucmedbio.2013.10.008. Epub 2013 Oct 29. PMID: 24373858.

The Development Of A Drug Discovery Platform

Holt PA, Ragazzon P, Strekowski L, Chaires JB, Trent JO.  Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform.  Nucleic Acids Research 2009 Mar;37(4):1280-7. PMID: 19136469. PMCID: PMC2651796.

Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A, Rasku MA, Arumugam S, Dean WL, Eaton J, Lane A, Trent JO, Chesney J.  Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth.  Molecular Cancer Therapy 2008 Jan;7(1):110-20. doi: 10.1158/1535-7163.MCT-07-0482. PMID: 18202014.

Winner M, Meier J, Zierow S, Rendon BE, Crichlow GV, Riggs R, Bucala R, Leng L, Smith N, Lolis E, Trent JO, Mitchell RA.  A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells.  Cancer Research 2008 Sep 15;68(18):7253-7. PMID: 18794110. PMCID: PMC2726006.

Clem BF, Clem AL, Yalcin A, Goswami U, Arumugam S, Telang S, Trent JO, Chesney J.  A novel small molecule antagonist of choline kinase-α that simultaneously suppresses MAPK and PI3K/AKT signaling.  Oncogene 2011 Jul 28;30(30):3370-80. Epub 2011 Mar 21. PMID: 21423211. PMCID: PMC3136659.

G-Protein Couple Receptors as Drug Targets. CXCR4 And BLT1

Trent JO, Wang ZX, Murray JL, Shao W, Tamamura H, Fujii N, Peiper SC.  Lipid bilayer simulations of CXCR4 with inverse agonists and weak partial agonists.  Journal of Biological Chemistry 2003 Nov 21;278(47):47136-44. Epub 2003 Sep 04. PMID: 12958314. [ http://www.jbc.org/content/278/47/47136.long ]

Compounds for Treating Disease, for Administering, and for Pharmaceutical Compositions.” U.S. Patent Number 8,785,490, Issued July 22, 2014. U.S. Patent Application ser. no. 14/289,712, Divisional of USPN 8,785,490; Allowed to Issue, June 2015.

Basu S, Jala VR, Mathis S, Rajagopal ST, Del Prete A, Maturu P, Trent JO, Haribabu B.  Critical role for polar residues in coupling leukotriene B4 binding to signal transduction in BLT1.  Journal of Biological Chemistry 2007 Mar 30;282(13):10005-17. Epub 2007 Jan 21. PMID: 17237498. [ http://www.jbc.org/content/282/13/10005.long ]

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