Laurence Hurley

Photo of Laurence Hurley

Laurence Hurley

Associate Director, BIO5 Institute
Professor, Medicinal Chemistry-Pharmaceutical Sciences
Professor, Medicinal Chemistry-Pharmacology and Toxicology
Professor, Cancer Biology - GIDP
Professor, BIO5 Institute
Primary Department
Pharmacology and Toxicology
Department Affiliations
Pharmacology and Toxicology
Contact
(520) 626-5622
lhurley@arizona.edu

Work Summary

Laurence Hurley's long-time research interest is in molecular targeting of DNA, first by covalent binders (CC-1065 and psorospermin), then as compounds that target protein–DNA complexes (pluramycins and Et 743), and most recently as four-stranded DNA structures (G-quadruplexes and i-motifs). He was the first to show that targeting G-quadruplexes could inhibit telomerase (Sun et al. [1997] J. Med. Chem., 40, 2113) and that targeting G-quadruplexes in promoter complexes results in inhibition of transcription (Siddiqui-Jain et al. [2002] Proc. Natl. Acad. Sci. U.S.A., 99, 11593).

Research Interest

Laurence Hurley, PhD, embraces an overall objective to design and develop novel antitumor agents that will extend the productive lives of patients who have cancer. His 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 at TGen at the Mayo Clinic in Scottsdale. Dr. Hurley directs 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. NMR and in vivo evaluations of novel agents are carried out in collaboration with other research groups in the Arizona Cancer Center. At present, they have a number of different groups of compounds that target a variety of intracellular receptors. These receptors include: (1) transcriptional regulatory elements, (2) those involved in cell signaling pathways, and (3) protein-DNA complexes, including transcriptional factor-DNA complexes.In close collaboration with Dr. Gary Flynn in Medicinal Chemistry, he has an ongoing program to target a number of important kinases, including aurora kinases A and B, p38, and B-raf. These studies involve structure-based approaches as well as virtual screening. Molecular modeling and synthetic medicinal chemistry are important tools.The protein–DNA complexes involved in transcriptional activation of promoter complexes using secondary DNA structures are also targets for drug design.

Publications

Hurley, L. H. (2002). DNA and its associated processes as targets for cancer therapy. Nature Reviews Cancer, 2(3), 188-200.

PMID: 11990855;Abstract:

DNA is the molecular target for many of the drugs that are used in cancer therapeutics, and is viewed as a non-specific target of cytotoxic agents. Although this is true for traditional chemotherapeutics, other agents that were discovered more recently have shown enhanced efficacy. Furthermore, a new generation of agents that target DNA-associated processes are anticipated to be far more specific and effective. How have these agents evolved, and what are their molecular targets?

Rezler, E. M., Seenisamy, J., Bashyam, S., Kim, M., White, E., Wilson, W. D., & Hurley, L. H. (2005). Telomestatin and diseleno sapphyrin bind selectively to two different forms of the human telomeric G-quadruplex structure. Journal of the American Chemical Society, 127(26), 9439-9447.

PMID: 15984871;Abstract:

The human telomeric sequence d[T2AG3]4 has been demonstrated to form different types of G-quadruplex structures, depending upon the incubation conditions. For example, in sodium (Na+), a basket-type G-quadruplex structure is formed. In this investigation, using circular dichroism (CD), biosensor-surface plasmon resonance (SPR), and a polymerase stop assay, we have examined how the addition of different G-quadruplex-binding ligands affects the conformation of the telomeric G-quadruplex found in solution. The results show that while telomestatin binds preferentially to the basket-type G-quadruplex structure with a 2:1 stoichiometry, 5,10,15,20-[tetra-(N-methyl-3-pyridyl)]-26-28-diselena sapphyrin chloride (Se2SAP) binds to a different form with a 1:1 stoichiometry in potassium (K+). CD studies suggest that Se2SAP binds to a hybrid G-quadruplex that has strong parallel and antiparallel characteristics, suggestive of a structure containing both propeller and lateral, or edgewise, loops. Telomestatin is unique in that it can induce the formation of the basket-type G-quadruplex from a random coil human telomeric oligonucleotide, even in the absence of added monovalent cations such as K+ or Na +. In contrast, in the presence of K+, Se2SAP was found to convert the preformed basket G-quadruplex to the hybrid structure. The significance of these results is that the presence of different ligands can determine the type of telomeric G-quadruplex structures formed in solution. Thus, the biochemical and biological consequences of binding of ligands to G-quadruplex structures found in telomeres and promoter regions of certain important oncogenes go beyond mere stabilization of these structures. © 2005 American Chemical Society.

Han, F. X., Wheelhouse, R. T., & Hurley, L. H. (1999). Interactions of TMPyP4 and TMPyP2 with quadruplex DNA. Structural basis for the differential effects on telomerase inhibition. Journal of the American Chemical Society, 121(15), 3561-3570.

Abstract:

The cationic porphyrins TMPyP4 and TMPyP2 possess similar structures but have strikingly different potencies for telomerase inhibition. To rationalize this difference, the interactions of TMPyP4 and TMPyP2 with an antiparallel quadruplex DNA were investigated. A single-stranded DNA oligonucleotide (G4A) containing four human telomere repeats of GGGTTA has been designed to form an intramolecular quadruplex DNA and was confirmed to form such a structure under 100 mM KCl by a DNA ligase assay, DMS footprinting, and CD spectrum analysis. By carrying out UV spectroscopic studies of the thermal melting profiles of G4A-porphyrin complexes, we provide evidence that TMPyP4 and TMPyP2 both stabilized quadruplex DNA to about the same extent. A photocleavage assay was used to determine the precise location for TMPyP4 and TMPyP2 in their interactions with quadruplex DNA. The results show that TMPyP4 binds to the intramolecular quadruplex DNA by stacking externally to the guanine tetrad at the GT step, while TMPyP2 binds predominantly to the same G4 DNA structure via external binding to the TTA loop. We propose that the inability of TMPyP2 to bind to the G4A by stacking externally to the guanine tetrad accounts for the differential effects on telomerase inhibition by TMPyP4 and TMPyP2.

Hurley, L., Kendrick, S., & Hurley, L. -. (2010). The role of G-quadruplex/i-motif secondary structures as cis-acting regulatory elements. Pure and applied chemistry. Chimie pure et appliquee, 82(8).

The nature of DNA has captivated scientists for more than fifty years. The discovery of the double-helix model of DNA by Watson and Crick in 1953 not only established the primary structure of DNA, but also provided the mechanism behind DNA function. Since then, researchers have continued to further the understanding of DNA structure and its pivotal role in transcription. The demonstration of DNA secondary structure formation has allowed for the proposal that the dynamics of DNA itself can function to modulate transcription. This review presents evidence that DNA can exist in a dynamic equilibrium between duplex and secondary conformations. In addition, data demonstrating that intracellular proteins as well as small molecules can shift this equilibrium in either direction to alter gene transcription will be discussed, with a focus on the modulation of proto-oncogene expression.

Kim, M., Duan, W., Gleason-Guzman, M., & Hurley, L. H. (2003). Design, synthesis, and biological evaluation of a series of fluoroquinoanthroxazines with contrasting dual mechanisms of action against topoisomerase II and G-quadruplexes. Journal of Medicinal Chemistry, 46(4), 571-583.

PMID: 12570378;Abstract:

Topoisomerase inhibitors are important and clinically effective drugs, while G-quadruplex-interactive compounds that disrupt telomere maintenance mechanisms have yet to be proven useful in the clinic. If G-quadruplex-interactive compounds are to be clinically useful, it will most likely be in combination with more established cytotoxic agents. We have previously reported on a family of topoisomerase II inhibitors that also interact with G-quadruplexes. On the basis of previously established structure-activity relationships (SARs) for compounds that are able to inhibit topoisomerase II or interact with G-quadruplex to varying degrees, we have now designed and synthesized four new fluoroquinoanthroxazines (FQAs) that have different profiles of mixed topoisomerase II poisoning effects and G-quadruplex interactions. The biological profiles of the four new compounds were determined with respect to G-quadruplex interaction (polymerase stop and photocleavage assays) and topoisomerase II interaction (DNA cleavage and kDNA decatenation assays), alongside cytotoxicity tests with matched pairs of topoisomerase II-resistant and topoisomerase II-sensitive cells and with telomerase (+) and ALT (+) cell lines (ALT = alternative lengthening of telomeres). From this study, we have identified two FQAs with sharply contrasting profiles of potent G-quadruplex interaction with a weak topoisomerase II poisoning effect, and vice versa, for further evaluation to determine the optimum combination of these activities in subsequent in vivo studies.

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