Laurence Hurley, PhD
The overall objective of the research projects in my laboratory is to design and develop novel antitumor agents that will extend the productive lives of patients who have cancer. My research program in medicinal chemistry depends upon a structure-based approach to drug design that is intertwined with clinical oncology programs in cancer therapeutics directed by Dr. Daniel Von Hoff at the Translational Genomics Research Institute (TGen), Dr. Scot Ebbinghaus and Dr. Robert Livingston at the Arizona Cancer Center. I direct a research group that consists of a team of graduate and postdoctoral students with expertise in structural and synthetic chemistry working alongside students in biochemistry and molecular biology. In vitro and in vivo evaluations of novel agents, as well as clinical trials, are carried out in collaboration with other research groups in the Arizona Cancer Center.
At present, we have a number of different groups of compounds that target a variety of intracellular receptors. The receptors include (1) promoter complexes and (2) those involved in cell signaling pathways. Examples of specific projects are given below.
1. Targeting Oncogene Promoters
We have established that a number of important oncogene promoters, including c-MYC, Bcl-2, VEGF, and PDGF-A, have guanine repeat regions that can form G-quadruplex structures, which can be specifically targeted by small molecules, leading to suppression of gene expression. We are exploring the molecular mechanisms for control of gene expression by G-quadruplexes and how G-quadruplex-interactive compounds modulate gene expression.
2. Targeting Protein Kinases
Using a structure-based approach, we are targeting a number of kinases, including aurora kinase A. This work involves molecular modeling, synthetic medicinal chemistry and molecular biology.
BPharm with Honors, Bath University, Bath, England, 1967, Pharmacy
PhD, Purdue University, 1970, Medicinal Chemistry
PD, University of British Columbia, Canada, 1970-1972, Chemistry Department
Honors and Awards
2008 American Association of Colleges of Pharmacy Paul Dawson Biotechnology Award
2007 Medicinal Chemistry Division Hall of Fame, American Chemical Society
2007 University of Arizona Innovator of the Year
2007 Kapp Lectureship, Virginia Commonwealth University
2006 American Chemical Society Medicinal Chemistry Hall of Fame
2005 George and Christine Sosnovsky Award in Cancer Therapy, Royal Society of Chemistry
2001 Frank Rose Memorial Lectureship, Leeds, England
1999 Prestige Lectureship, Bradford University, England
1997 Otto M. Smith Lectureship, Oklahoma State University
1996 DSc, Bath University, England
1994 American Chemical Society Medicinal Chemistry Award
1994 John Albert Southern Lecturer, Furman University
1994 NCI Outstanding Investigator Award
1992 MIKI Keynote Speaker
1992 APhA Research Achievement Award in Medicinal Chemistry
1991 University of Georgia Medicinal Chemistry Lecture Series
1990 Watkins Visiting Professorship, Wichita State University
1990 AAAS Fellow
1989 NCI Outstanding Investigator Award
1989 Volwiler Research Achievement Award
1988 Distinguished Alumnus Award, Purdue University School of Pharmacy and Pharmacal Sciences
1988 George H. Hitchings Award in Innovative Methods for Drug Design
1987 Ole Gisvold Lectureship, University of Minnesota
1982 Julius Koch Memorial Lecturer, University of Pittsburgh
Gerner, E. W.; Ignatenko, N. A.; Lance, P.; Hurley, L. H. (2005) A comprehensive strategy to combat colon cancer targeting the adenomatous polyposis coli tumor suppressor gene. Ann. N.Y. Acad. Sci., 1059, 97–105.
Hurley, L. H.; Von Hoff, D. D.; Siddiqui-Jain, A.; Yang, D. (2006) Drug targeting of the c-MYC promoter to repress gene expression via a G-quadruplex silencer element. Sem. Oncol., 33, 498–512.
Dexheimer, T. S.; Sun, D.; Hurley, L. H. (2006) Deconvoluting the structural and drug-recognition complexity of the G-quadruplex-forming region upstream of the bcl2 P1 promoter. J. Am. Chem. Soc., 128, 5404–5415.
De Armond, R.; Wood, S.; Sun, D.; Hurley, L. H.; Ebbinghaus, S. (2005) Evidence for the presence of a guanine quadruplex forming region within a polypurine tract of the hypoxia inducible factor 1 promoter. Biochemistry, 44, 16341–16350.
Warner, S. L.; Bashyam, S.; Vankayalapati, H.; Bearss, D. J.; Han, H.; Von Hoff, D. D.; Hurley, L. H. (2006) Identification of a Lead Small Molecule Inhibitor of the Aurora Kinases Using a Structure-Assisted, Fragment-Based Approach. Mol. Cancer Ther., 5, 1764–1773.
Warner, S. L.; Muñoz, R. M.; Stafford, P.; Koller, E.; Hurley, L. H.; Nagle, R. B.; Von Hoff, D. D.; Han, H. (2006) Comparing aurora A and aurora B as targets for growth inhibition of pancreatic cancer cells. Mol. Cancer Ther., 5, 2450–2458.
Hahn, T.; Szabo, L.; Gold, M.; Ramanathapuram, L.; Hurley, L. H.; Akporiaye, E. T. (2006) Dietary administration of the proapoptotic vitamin E analogue -tocopheryloxyacetic acid inhibits metastatic murine breast cancer. Cancer Res., 66, 9374–9378.
Zhu, M.; Gokhale, V. M.; Szabo, L.; Muñoz, R. M.; Baek, H.; Bashyam, S.; Hurley, L. H.; Von Hoff, D. D.; Han, H. (2007) Identification of a novel inhibitor of urokinase-type plasminogen activator. Mol. Cancer Ther., 6, 1348–1356.
Freyer, M. W.; Buscaglia, R.; Kaplan, K.; Cashman, D.; Hurley, L. H.; Lewis, E. A. (2007) Biophysical studies of the c-MYC NHE III1 promoter: model quadruplex interactions with a cationic porphyrin. Biophys. J., 92, 2007–2015.
Guo, K.; Pourpak, A.; Beetz-Rogers, K.; Gokhale, V.; Sun, D.; Hurley, L. H. (2007) Formation of G-quadruplex and i-motif structures in the proximal promoter region of the RET oncogene. J. Am. Chem. Soc., submitted.
Qin, Y.; Rezler, E. M.; Gokhale, V.; Sun, D.; Hurley, L. H. (2007) Characterization of the G-quadruplexes in the duplex nuclease hypersensitive element of the PDGF-A promoter and modulation of PDGF-A promoter activity by TMPyP4. Nucleic Acids Res., submitted.
Dexheimer, T. S.; Gokhale, V. M.; Hu, X.; Murata, L. B.; Maes, E. M.; Weichsel, A.; Sun, D.; Montfort, W. R.; Hurley, L. H. (2007) Elucidation of the role of NM23-H2/NDP kinase B in activation of c-myc transcription through the G-quadruplex-forming element. J. Biol. Chem., submitted.
Sun, D. and Hurley, L.H. "The mechanism of action of telomestatin, a G-quadruplex-interactive compound," in Sequence Specific DNA Binding Agents, ed. M. Waring, Royal Society of Chemistry, RSCPublishing, Cambridge; pp. 207-232. (2006).
Dai, J., Chen, D., Jones, R.A., Hurley, L.H., Yang, D. NMR solution structure of the major G-quadruplex structure formed in the human bcl-2 promoter region. Nucleic Acids Res., 34, 5133-5144(2006).
Dexheimer, T.S., Sun, D., Fry, M., Hurley, L.H. "DNA quadruplexes and gene regulation," Quadruplex Nucleic Acids, ed. S. Neidle, Royal Society of Chemistry, RSCPublishing, Cambridge; pp. 180-207 (2006).
D. Yang, L. H. Hurley. Structure of the Biologically Relevant G-Quadruplex in the c-MYC Promoter. Nucleosides, Nucleotides, Nucleic Acids, 25, 951-968 (2006).
W. Liu, L. H. Hurley, D. Sun. Binding of G-Quadruplex-Interactive Agents to Distinct G-Quadruplexes Induces Different Biological Effects in MiaPaCa Cells. Nucleosides, Nucleotides, Nucleic Acids, in press, 24, 1801-1815 (2005).
E. M. Rezler, V. Gokhale, J. Seenisamy, S. Bashyam, M.-Y. Kim, L. H. Hurley. Telomestatin and Diselenosapphyrin Bind Selectively to Two Different Forms of the Human Telomeric G-Quadruplex Structure. J. Am. Chem. Soc., 127, 9339-9347.
J. Seenisamy, S. Bashyam, V. Gokhale, H. Vankayalpati, D. Sun, A. Siddiqui-Jain, N. Streiner, K. Shin-ya, E. White, W. D. Wilson, L. H. Hurley. Design and Synthesis of an Expanded Porphyrin That Has Selectivity for the c-MYC G-Quadruplex Structure. J. Am. Chem. Soc. 127, 2944–2959 (2005).
R. Heald, T. S. Dexheimer, H. Vankayalapati, A. Siddiqui-Jain, M. Gleason-Guzman, L. H. Hurley. Conformationally Restricted Analogues of Psorospermin: Design, Synthesis, and Bioactivity of Natural Product–Related Bisfuranoxanthones. J. Med. Chem. 48, 2993–3004 (2005).
J. Seenisamy, E. M. Rezler, V. Gokhale, A. Siddiqui-Jain, D. Tye, T. J. Powell, L. H. Hurley. The Dynamic Character of the G-Quadruplex Element in the c-MYC Promoter and Modification by TMPyP4. J. Am. Chem. Soc. 126, 8702–8709 (2004).
M. A. Shammas, R. J. Shmookler Reis, M. Akiyama, H. Koley, D. Chauhan, T. Hideshima, R. K. Goyal, L. H. Hurley, K. C. Anderson, N. C. Munshi. Telomerase Inhibition and Cell Growth Arrest by G-Quadruplex Interactive Agent in Multiple Myeloma. Mol. Cancer Ther. 2, 825–833 (2003).
M.-Y. Kim, W. Duan, M. Gleason-Guzman, L. H. Hurley. Design, Synthesis, and Biological Evaluation of a Series of Fluoroquinoanthroxazines with Contrasting Dual Mechanisms of Action against Topoisomerase II and G-Quadruplexes. J. Med. Chem. 46, 571–583 (2003).