John O. Trent, Ph.D.
Associate Professor of Medicine, Chemistry and Biochemistry
Email John Trent
Phone Number: (502) 852 2194 (Office)
Fax Number: (502) 852 4311
Address: Suite 323, J.G. Brown Cancer Center
527 South Jackson St. Louisville, KY 40202
Ph. D. 1992, University of Canterbury, New Zealand
- Associate Professor, Division of Hematology/Oncology, Dept. of Medicine
- Associate Professor, Division of Internal Medicine, Department of Medicine
- Wendell Cherry Endowed Chair in Cancer Translational Research
- Director, Kosair Pediatric Oncology Research Program
- Director, Molecular Modeling Facility, James Graham Brown Cancer Center
- Indira Chaudhuri - Postdoctoral Fellow
- Rafael Del Villar Guerra - Postdoctoral Fellow
- Huy Le - MD/PhD student
- Structure-based drug design, macromolecular molecular dynamics modeling of proteins, DNA and RNA drug discovery.
- My group uses numerous computational techniques to complement experimental approaches aimed at understanding macromolecular interactions. The methods include molecular dynamics, free energy perturbation calculations, and Monte-Carlo methods as applied to real world problems. The combination of modeling techniques with different experimental modalities such as NMR, X-ray diffraction and thermodynamic methods is synergistic, and is the key to understanding structure and function. We have successfully modeled the structure of the nucleolin binding quadruplex, as verified by biophysical studies such as CD (with P. Bates), analytical ultracentrifugation and NMR (with A. Lane). We also have produced detailed rhodopsin-based homology models of the CCR5 and CXCR4 chemokine receptors, embedded in a complete, solvated lipid bilayer, that successfully account for the saturation mutation data obtained by Dr. S. C. Peiper at the Brown Cancer Center (now at Georgia Medical College, Augusta). We have a strong interest in quadruplex structure and as a drug target and collaborate with Dr. J. B. Chaires on the biophysical aspect of this work.
- We also have enhanced our drug discovery program by establishing a distributing computing Grid for virtual screening. The Grid development is in collaboration with Dataseam and uses thousands of computer processors in schools across the Commonwealth of Kentucky. It is now routine in my laboratory to screen millions of potential compounds against a cancer target in days. We have successfully screened over 60 cancer targets that are moving into the laboratories for anticancer activity testing.
- Gray RD, Petraccone L, Trent JO, Chaires JB. Characterization of a K+-induced conformational switch in a human telomeric DNA oligonucleotide using 2-aminopurine fluorescence. Biochemistry. 2010 Jan 12;49(1):179-94.
- Petraccone L, Garbett NC, Chaires JB, Trent JO.An integrated molecular dynamics (MD) and experimental study of higher order human telomeric quadruplexes. Biopolymers. 2010 Jun;93(6):533-48.
- 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 Res. 2010 Mar 25.
- Arumugam S, Miller MC, Maliekal J, Bates PJ, Trent JO, Lane AN. Solution structure of the RBD1,2 domains from human nucleolin. J Biomol NMR. 2010 May;47(1):79-83.
- Cunningham AR, Qamar S, Carrasquer CA, Holt PA, Maguire JM, Cunningham SL, Trent JO. Mammary carcinogen-protein binding potentials: novel and biologically relevant structure-activity relationship model descriptors. SAR QSAR Environ Res. 2010 Jul;21(5):463-79.
- 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)).J Am Chem Soc. 2010 Nov 18.
- 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. doi: 10.1038/onc.2011.51.
- Chaires, Jonathan B., Miller, M. Clarke,Buscaglia, Robert,Gray, Robert D., Lane, Andrew N., Trent, John O., CHEMICAL & ENGINEERING NEWS Volume: 89 Issue: 32 Pages: 66 Published: AUG 8 2011
- Miller MC, Le HT, Dean WL, Holt PA, Chaires JB, Trent JO. Polymorphism and resolution of oncogene promoter quadruplex-forming sequences. Org Biomol Chem. 2011 Sep 21.
- Holt PA, Buscaglia R, Trent JO, Chaires JB. A Discovery Funnel for Nucleic Acid Binding Drug Candidates. Drug Dev Res. 2011 Mar 1;72(2):178-186.
- Petraccone L, Spink C, Trent JO, Garbett NC, Mekmaysy CS, Giancola C, Chaires JB. Structure and stability of higher-order human telomeric quadruplexes. J Am Chem Soc. 2011 Dec 28;133(51):20951-61.
- Cunningham AR, Carrasquer CA, Qamar S, Maguire JM, Cunningham SL, Trent JO. Global structure-activity relationship model for non-mutagenic carcinogens using virtual ligand protein interactions as model descriptors. Carcinogenesis. 2012 Jun 7. [Epub ahead of print] Oct;33(10):1940-5.
- Telang S, Clem BF, Klarer AC, Clem AL, Trent JO, Bucala R, Chesney J. Small Molecule Inhibition of 6-Phosphofructo-2-Kinase Suppresses T Cell Activation. J Transl Med. 2012 May 16;10(1):95.
- 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. Org Biomol Chem. 2012 Dec 21;10(47):9393-404.
- Clem BF, O'Neal J, Tapolsky G, Clem AL, Imbert-Fernandez Y, Kerr DA 2nd, Klarer A, Redman R, Miller DM, Trent JO, Telang S, Chesney J Targeting 6-Phosphofructo-2-Kinase (PFKFB3) as a Therapeutic Strategy against Cancer. Mol Cancer Ther. 2013 May 14. [Epub ahead of print]
- Snyder RD, Holt PA, Maguire JM, Trent JO.Prediction of noncovalent Drug/DNA interaction using computational docking models: Studies with over 1350 launched drugs. Environ Mol Mutagen. 2013 Jul 26:1-15.
Patents & Licenses:
- 12-Feb-10 Treatment of Age-Related Macular Degeneration Using a Molecular Antagonist of MIF, 61/396,009 (prov. appln), Robert Mitchell, John Trent, Tongalp Tezel, Henry Kaplan
- 28-May-10 ANAPC11 as a Target for Chemotherapy, J. Christopher States, Ben Frazier, John Trent
- 13-Jun-11 A New Method for the Diagnosis and Prognosis of Malignant Diseases "7,541,150 (US -issued) PCT/US03/10745 (PCT) 2003-583205 (Japan) 2003234694 (Australia-issued) 2,490,724 (Canada-Issued) 3728350.4 (EU) Validation-France Validation-Germany Validation-Italy Validation-Spain Validation-United Kingdom CIP FAMILY 7,357,928 (US-CIP issued) 12/041,969 (USA-CIP) PCT/US04/033174 (PCT-CIP) 2,546,730 (Canada-CIP) 2004279837 (Australia-CIP) 4785392.4 (EU-CIP) 2006-534360 (Japan-CIP) 7101518.4 (Hong Kong-CIP) The CIP family (treatment claims) are licensed to CharlestonPharma (March 2011). A license to the original, parental family (diagnostic claims) is currently under negotiation with CharlestonPharma.
- 24-Aug-10 Mammory Carcinogen-Protein Binding Potentials: Novel and Biologically Relevant Structure-Activity Relationship Model Descriptors 61/380,048 (prov. appln), PCT/US11/50350, 13/224,915 (U.S. nonprov) Albert R. Cunningham, John O. Trent To be optioned by Gnarus
- 12-Oct-10 Identification of a Novel Small Molecule Antagonist of the MIF Homolog, D-Dopachrome Tautomerase. Robert A. Mitchel, John O. Trent, research disclosure with OTT
- 20-Nov-11 Use of a Novel Lactate Dehydrogenase A Inhibitor 5-[(3R)-3-(2-Chloro-6-Methoxyquinolin-3-YL)-5-(4-Chlorophenyl)-3,4-Dihydropyrazol-2-YL]-5-Oxopentanoate (termed CCDO-1; Zinc09043798), for the Treatment of Cancer Jason Chesney, John Trent, Sucheta Telang, Brian Clem, research disclosure with OTT
- 5-Dec-11 Identification and Validation of Novel Arylamine N-Acetyltransferase Small Molecule Inhibitors Mark A. Doll, David W. Hein, Carmine Leggett, John O. Trent, Jason Walraven research disclosure with OTT; prior art search underway (2012)
- 21-Dec-11 Promoting Tumor Cell Apoptosis by Directly Activating the Pro-Apoptotic Bel-2 Protein Bax Chi Li, John O. Trent, research disclosure with OTT
- 10-May-12 Targeted Inhibition of Karyopherin B-Mediated Nuclear Transport (KpnB1) Using Small Molecule Inhibitors Virna Leaner, John Trent joint research disclosure with University of Capetown, S.A.