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:

Professor of Medicine, Chemistry, 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, molecular modeling, biophysics, and 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 (1-8), triplex (9-15), and particularly quadruplex (16-36) 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 are towards targeting the biologically relevant quadruplex regions of the human telomere and oncogene promoters in collaboration with Dr. Brad Chaires.

We are also heavily involved in the discovery of new therapeutics against protein targets, such as CCR5 (37-39), CXCR4 (40-49), nucleolin (50), 6-phosphofructo-2-kinase (51-53), choline kinase (54), Bcl-2 (55), and macrophage inhibitory factor (56, 57). 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, so that we can routinely computationally screen tens of millions of compounds against any particular target of interest.

Literature Cited:

  1. J. O. Trent, G. R. Clark, A. Kumar, W. D. Wilson, D. W. Boykin, J. E. Hall, R. R. Tidwell, B. L. Blagburn, S. Neidle, Targeting the minor groove of DNA: crystal structures of two complexes between furan derivatives of berenil and the DNA dodecamer d(CGCGAATTCGCG)2. Journal of medicinal chemistry39, 4554-4562. (1996).
  2. A. A. Wood, C. M. Nunn, J. O. Trent, S. Neidle, Sequence-dependent crossed helix packing in the crystal structure of a B-DNA decamer yields a detailed model for the Holliday junction. J. Mol. Biol., 269, 827-841 (1997).
  3. X. Qu, J. O. Trent, I. Fokt, W. Priebe, J. B. Chaires, From the cover: allosteric, chiral-selective drug binding to DNA. Proc Natl Acad Sci U S A, 97, 12032-12037. (2000).
  4. W. Priebe, I. Fokt, T. Przewloka, J. B. Chaires, J. Portugal, J. O. Trent, Exploiting anthracycline scaffold for designing DNA-targeting agents. Methods in enzymology, 340, 529-555 (2001).
  5. J. I. Gyi, D. Gao, G. L. Conn, J. O. Trent, T. Brown, A. N. Lane, The solution structure of a DNA*RNA duplex containing 5-propynyl U and C; comparison with 5-Me modifications. Nucleic Acids Res, 31, 2683-2693 (2003).
  6. J. Booth, T. Brown, S. J. Vadhia, O. Lack, W. J. Cummins, J. O. Trent, A. N. Lane, Determining the origin of the stabilization of DNA by 5-aminopropynylation of pyrimidines. Biochemistry, 44, 4710-4719 (2005).
  7. J. Portugal, D. J. Cashman, J. O. Trent, N. Ferrer-Miralles, T. Przewloka, I. Fokt, W. Priebe, J. B. Chaires, A new bisintercalating anthracycline with picomolar DNA binding affinity. Journal of medicinal chemistry, 48, 8209-8219 (2005).
  8. P. A. Holt, J. B. Chaires, J. O. Trent, Molecular docking of intercalators and groove-binders to nucleic acids using Autodock and Surflex. Journal of chemical information and modeling, 48, 1602-1615 (2008).
  9. S. A. Cassidy, P. Slickers, J. O. Trent, D. C. Capaldi, P. D. Roselt, C. B. Reese, S. Neidle, K. R. Fox, Recognition of GC base pairs by triplex forming oligonucleotides containing nucleosides derived from 2-aminopyridine. Nucleic Acids Res, 25, 4891-4898. (1997).
  10. C. M. Nunn, J. O. Trent, S. Neidle, A model for the [C+-GxC]n triple helix derived from observation of the C+-GxC base triplet in a crystal structure. FEBS letters, 416, 86-89 (1997).
  11. M. D. Keppler, M. A. Read, P. J. Perry, J. O. Trent, T. C. Jenkins, A. P. Reszka, S. Neidle, K. R. Fox, Stabilization of DNA triple helices by a series of mono- and disubstituted amidoanthraquinones. Eur. J. Biochem., 263, 817-825 (1999).
  12. J. Basye, J. O. Trent, D. Gao, S. W. Ebbinghaus, Triplex formation by morpholino oligodeoxyribonucleotides in the HER- 2/neu promoter requires the pyrimidine motif. Nucleic Acids Res, 29, 4873-4880. (2001).
  13. N. Vigneswaran, J. Thayaparan, J. Knops, J. Trent, V. Potaman, D. M. Miller, W. Zacharias, Intra- and intermolecular triplex DNA formation in the murine c-myb proto-oncogene promoter are inhibited by mithramycin. Biol Chem382, 329-342. (2001).
  14. Z. V. Zhilina, A. J. Ziemba, J. O. Trent, M. W. Reed, V. Gorn, Q. Zhou, W. Duan, L. Hurley, S. W. Ebbinghaus, Synthesis and evaluation of a triplex-forming oligonucleotide-pyrrolobenzodiazepine conjugate. Bioconjugate chemistry, 15, 1182-1192 (2004).
  15. P. A. Holt, P. Ragazzon, L. Strekowski, J. B. Chaires, J. O. Trent, Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform. Nucleic Acids Res, 37, 1280-1287 (2009).

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