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 a clinical oncology program in cancer therapeutics directed by Professor Daniel Von Hoff in 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 Intra- cellular receptors.The receptors include (1) those involved in cell signaling pathways, (2) protein-DNA complexes, includi ng topoisomerase II-DNA complexes, (3) promoter complexes, and (4) telomeres and telomerase. Examples of specific projects are given below.
1. Telomere maintenance mechanisms: We are designing drugs that will specifically target different features of the t-loop structure present at the ends of human chromosomes. These t-loop structures include the "invasion complex," TRF-1-DNA and TRF-2-DNA complexes, and telomeric DNA.
2. Promoter regions: We are specifically interested in drug targeting of oncogene promoter regions that may contain architecturally modified DNA and secondary DNA structures such as G-quadruplexes.
3. Topoisomerase II-DNA complexes: A longstanding unsolved problem in structural biology that has direct application to the design and synthesis of new antibacterial and anticancer agents is how drugs such as the fluoroquinolones interact with gyrase-DNA complexes and topoisomerase II-DNA complexes in precise molecular terms. Our goal is to solve this problem using a multi-disciplinary approach involving the synthesis of stable isotope-labeled DNA, topoisomerase II, and drug molecules that will be used in combination with REDOR NMR. Two groups of topo II interactive drugs (psorospermin, quinolones) are currently under investigation.
4. Cross-talk between cytotoxic agents, such as topo II inhibitors, and downstream modulators of cell cycle checkpoints: The next generation of cancer therapeutic agents will involve combinations of specific agents that work in a synergistic manner.As a precursor to this, an important correlation between drug-modified patterns of gene expression and in vivo activity and clinical outcome needs to be established. We have designed and synthesized dual mechanism of action compounds in which the two different receptor interactions can be separately modulated. A set of compounds with predetermined levels of each of the dual activities will be evaluated for effects on gene expression and for in vitro and in vivo activity.It is anticipated that select compounds will be evaluated clinically.
A number of anticancer agents in phase I and phase II clinical trials have an unknown mechanism of action, e.g., Et 743, HMAF, and Bizelesin. Ongoing studies in my laboratory are aimed at elucidating the molecular mechanisms of action of these compounds.
H. Han, and L. H. Hurley. G-Quadruplex DNA: a Potential Target for Anticancer Drug Design. Trends Pharm. Sci., 21:136-142, 2000.
M. Zewail-Foote and L. H. Hurley. Molecular Approaches to Achieving Control of Gene Expression by Drug Intervention at the Transcriptional Level. Anti-Cancer Drug Des. 14:1-9, 1999.
S. Borman. Speedy Route to Folded DNA. C&E News 77, 36-37, 1999.
M. Hansen and L. H. Hurley. Pluramycins. Old Drugs Having Modern Friends in Structural Biology. Acc. Chem. Res. 29:249-258, 1996.
O. Yu. Fedoroff, A. Rangan, V. V. Chemeris, and L. H. Hurley. Cationic Porphyrins Promote the Formation of i-Motif DNA and Bind Peripherally by a Nonintercalative Mechanism. Biochemistry, 39:15083-15090, 2000.
F. C. Seaman and L. H. Hurley. Molecular Basis for the DNA Sequence Selectivity of Ecteinascidin 736 and 743: Evidence for the Dominant Role of Direct Readout via Hydrogen Bonding. J. Am. Chem. Soc. 120:13028-13041, 1998.
M. Zewail-Foote and L. H. Hurley. Ecteinascidin 743: A Minor Groove Alkylator That Bends DNA toward the Major Groove. J. Med. Chem. 42:2943-2497, 1999.
O. Yu. Fedoroff, M. Salazar, H. Han. V. V. Chemeris, S. M. Kerwin, and L. H. Hurley. NMR-Based Model of a Telomerase-Inhibiting Compound Bound to G-Quadruplex DNA. Biochemistry 37:12367-12374, 1998.
Telomeres and Telomerase:
A. Rangan, O. Yu. Fedoroff, and L. H. Hurley. Induction of Duplex to G-Quadruplex Transition in the c-myc Promoter Region by a Small Molecule. J. Biol. Chem., in press, 2001.
F. X. Han, R. T. Wheelhouse, and L. H. Hurley. Interactions of TMPyP4 and TMPyP2 with Quadruplex DNA. Structural Basis for the Differential Effects on Telomerase Inhibition. J. Am. Chem. Soc. 121:3561-3570, 1999.
H. Han, C. L. Cliff, and L. H. Hurley. Accelerated Assembly of G-Quadruplex Structures by a Small Molecule. Biochemistry 38:6981-6986, 1999.
E. Izbicka, R. T. Wheelhouse, E. Raymond, K. K. Davidson, R. A. Lawrence, D. Sun, B. E. Windle, L. H. Hurley, and D. D. Von Hoff. Effects of Cati onic Porphyrins as G-Quadruplex-Interactive Agents in Human Tumor Cells. Cancer Res. 59:639-644, 1999.
H. Han, R. J. Bennett, and L. H. Hurley. Inhibition of Unwinding of G-Quadruplex Structures by Sgs1 Helicase in the Presence of N,N'-Bis[2-(1-piperidino)ethyl]-3,4,9,10-perylenetetracarboxylic Diimide, a G-Quadruplex-Interactive Ligand. Biochemistry, 39:9311-9316, 2000.
S.-J. Lee and L. H. Hurley. A Thymine:Thymine Mismatch Enhances the Pluramycin Alkylation Site Downstream of the TBP-TATA Box Complex. J. Am. Ch em. Soc. 121:8971-8977, 1999.
Y. Kwok, Q. Zeng, and L. H. Hurley. Structural Insight into a Quinolone-Topoisomerase-DNA Complex: Evidence for a 2:2 Quinobenzoxazine:Mg2+ Self-Assembly Complex in the Presence of Topoisomerase II. J. Biol. Chem. 274:17226-17235, 1999.
Y. Kwok, Q. Zeng, and L. H. Hurley. Topoisomerase II-Mediated Site-Directed Alkylation of DNA by Psorospermin and Its Use in Mapping Other Topoisomerase II Poison Binding Sites. Proc. Natl. Acad. Sci. U.S.A. 95:13531-13536, 1998.