Discovery and development of novel anticancer drugs; transcriptional
control; telomeres; telomerase; topoisomerases as drug targets.
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. We also have close ties with a biotech
startup company, Cyternex, Inc.
At present, we have a number of different groups of compounds
that target a variety of intracellular receptors. The receptors
include (1) those involved in cell signaling pathways, (2) protein-DNA
complexes, including topoisomerase II-DNA complexes, (3) promoter
complexes, and (4) telomeres and telomerase. Examples of specific
projects are given below.
1. Targeting transcriptional control: We are specifically interested
in drug targeting of oncogene promoter regions that contain architecturally
modified DNA and secondary DNA structures such as G-quadruplexes.
2. 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.
3. Targeting protein-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 multidisciplinary approach
involving the synthesis of stable isotope-labeled DNA, topoisomerase
II, and drug molecules that will be used in combination with NMR.
Two groups of topo II interactive drugs (psorospermin, quinolones)
are currently under investigation. (see reference XXX).
4. Dual mechanism of action: 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.
Reviews:
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.
L. H. Hurley. DNA and Associated Processes as Targets for Cancer
Therapy. Nat. Rev. Cancer 2:188-200 (2002).
E. M. Rezler, D. J. Bearss, and L. H. Hurley. Telomeres and Telomerases
as Drug Targets. Curr. Opin. Pharmacol. 2:415-423, 2002.
E. M. Rezler, D. J. Bearss, and L. H. Hurley. Telomere Inhibition
and Telomere Disruption as Processes for Drug Targeting. Annu.
Rev. Pharmacol. Toxicol., 2002, in press.
Targeting Telomeres and Telomerase:
H. Han, A. Rangan, D. R. Langley, and L. H. Hurley. Selective
Interaction of Cationic Porphyrins with G-Quadruplex Structures.
J. Am. Chem. Soc. 123:8902-8913, 2001.
D.-F. Shi, R. T. Wheelhouse, D. Sun, and L. H. Hurley. Quadruplex-Interactive
Agents as Telomerase Inhibitors: Synthesis of Porphyrins and Structure-Activity
Relationship for the Inhibition of Telomerase. J. Med. Chem. 44:4509-4523,
2001.
M.-Y. Kim, H. Vankayalapati, K. Shin-ya, K. Wierzba, and L. H.
Hurley. Telomestatin, a Potent Telomerase Inhibitor That Interacts
Quite Specifically with the Human Telomeric Intramolecular G-Quadruplex.
J. Am. Chem. Soc. 124:2098-2099, 2002.
Dual Mechanism of Action:
W. Duan, A. Rangan, H. Vankayalapati, M.-Y. Kim, Q. Zeng, D. Sun,
H. Han, O. Yu. Fedoroff, D. Nishioka, S. Y. Rha, E. Izbicka, D.
D. Von Hoff, and L. H. Hurley. Design and Synthesis of Fluoroquinophenoxazines
That Interact with Human Telomeric G-Quadruplexes and Their Biological
Effects. Molecular Cancer Therapeutics 1:103-120 (2001).
M.-Y. Kim, W. Duan, M. Gleason-Guzman, and 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., in press (2002).
Protein-DNA Complexes:
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.
M. Zewail-Foote, V.-S. Li, H. Kohn, D. Bearss, M. Guzman, and
L. H. Hurley. The Inefficiency of Incisions of Ecteinascidin 743-DNA
Adducts by the UvrABC Nuclease and the Unique Structural Feature
of the DNA Adducts Can Be Used To Explain the Repair-Dependent
Toxicities of This Antitumor Agent. Chem. Biol. 8:1033-1049, 2001.
[Highlighted in C&E News 79:41, 2001.]
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.
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.
