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
Department Affiliations
Contact
(520) 626-5622

Work Summary

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

Hahn, T., Bradley-Dunlop, D. J., Hurley, L. H., Von-Hoff, D., Gately, S., Mary, D. L., Lu, H., Penichet, M. L., Besselsen, D. G., Cole, B. B., Meeuwsen, T., Walker, E., & Akporiaye, E. T. (2011). The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer. BMC cancer, 11.
BIO5 Collaborators
David G Besselsen, Laurence Hurley

HER2/neu is an oncogene that facilitates neoplastic transformation due to its ability to transduce growth signals in a ligand-independent manner, is over-expressed in 20-30% of human breast cancers correlating with aggressive disease and has been successfully targeted with trastuzumab (Herceptin®). Because trastuzumab alone achieves only a 15-30% response rate, it is now commonly combined with conventional chemotherapeutic drugs. While the combination of trastuzumab plus chemotherapy has greatly improved response rates and increased survival, these conventional chemotherapy drugs are frequently associated with gastrointestinal and cardiac toxicity, bone marrow and immune suppression. These drawbacks necessitate the development of new, less toxic drugs that can be combined with trastuzumab. Recently, we reported that orally administered alpha-tocopheryloxyacetic acid (α-TEA), a novel ether derivative of alpha-tocopherol, dramatically suppressed primary tumor growth and reduced the incidence of lung metastases both in a transplanted and a spontaneous mouse model of breast cancer without discernable toxicity.

Galbraith, D. W., Bourque, D. P., & Bohnert, H. J. (1995). Preface. Methods in Cell Biology, 50(C), xxi-xxii.
BIO5 Collaborators
David W Galbraith, Laurence Hurley
Jacobson, M. K., Twehous, D., & Hurley, L. H. (1986). Depletion of nicotinamide adenine dinucleotide in normal and xeroderma pigmentosum fibroblast cells by the antitumor drug CC-1065. Biochemistry, 25(20), 5929-5932.

PMID: 3790494;Abstract:

CC-1065 is an extremely potent antitumor antibiotic that forms a well-defined adduct with DNA in which the molecule lies within the minor groove and is covalently attached through N3 of adenine. Addition of CC-1065 to human fibroblast cells produced a prolonged depletion of the nicotinamide adenine dinucleotide (NAD) pool even at extremely low drug concentrations (0.01 μg/mL). The depletion of NAD by CC-1065 was blocked by 3-aminobenzamide, which is consistent with a NAD depletion mechanism involving poly-(ADP-ribose) synthesis in response to a repair-induced DNA strand breakage event. Significantly, similar extents of NAD depletion were also evident in xeroderma pigmentosum cells of complementation groups A and D following exposure to CC-1065. Since this NAD depletion is presumably associated with repair-induced incision, the repair of CC-1065-DNA adducts can probably take place by a pathway distinct from that involved in repair of more conventional bulky DNA adducts. The prolonged depletion of NAD, even at low doses of drug, suggests that CC-1065 causes DNA damage that results in a delay or block in DNA excision repair between the excision and ligation steps. © 1986 American Chemical Society.

Izbicka, E., Wheelhouse, R. T., Raymond, E., Davidson, K. K., Lawrence, R. A., Sun, D., Windle, B. E., Hurley, L. H., & D., D. (1999). Effects of cationic porphyrins as G-quadruplex interactive agents in human tumor cells. Cancer Research, 59(3), 639-644.

PMID: 9973212;Abstract:

A series of cationic porphyrins has been identified as G-quadruplex interactive agents (QIAs) that stabilize telomeric G-quadruplex DNA and thereby inhibit human telomerase; 50% inhibition of telomerase activity was achieved in HeLa cell-free extract at porphyrin concentrations in the range ≤50 μM. Cytotoxicity of the porphyrins in vitro was assessed in normal human cells (fibroblast and breast) and human tumor cells representing models selected for high telomerase activity and short telomeres (breast carcinoma, prostate, and lymphoma). In general, the cytotoxicity (EC50, effective concentration for 50% inhibition of cell proliferation) against normal and tumor cells was >50 μM. The porphyrins were readily absorbed into tumor cell nuclei in culture. Inhibition of telomerase activity in MCF7 cells by subcytotoxic concentrations of TMPyP4 showed time and concentration dependence at 1-100 μM TMPyP4 over 15 days in culture (10 population doubling times). The inhibition of telomerase activity was paralleled by a cell growth arrest in G2-M. These results suggest that relevant biological effects of porphyrins can be achieved at concentrations that do not have general cytotoxic effects on cells. Moreover, the data support the concept that a rational, structure-based approach is possible to design novel telomere-interactive agents with application to a selective and specific anticancer therapy.

Zhilina, Z. V., Ziemba, A. J., Trent, J. O., Reed, M. W., Gorn, V., Zhou, Q., Duan, W., Hurley, L., & Ebbinghaus, S. W. (2004). Synthesis and evaluation of a triplex-forming oligonucleotide- pyrrolobenzodiazepine conjugate. Bioconjugate Chemistry, 15(6), 1182-1192.

PMID: 15546183;Abstract:

In most cases, unmodified oligonucleotides designed as antigene molecules are incapable of binding to DNA with sufficient stability to prevent gene expression. To stabilize binding to a polypurine tract in the HER-2/neu promoter, a triplex forming oligonucleotide (TFO) was conjugated to a pyrrolo[1,4]-benzodiazepine (PBD), desmethyltomaymycin, and site-specific DNA binding was evaluated. An activated ester of the PBD moiety was conjugated by an acylation reaction to a free primary amine on a 50-atom aliphatic linker at the 5' end of the TFO. This long aliphatic linker was designed to provide a bridge from the major groove binding site of the TFO to the minor groove binding site of the PBD. Triplex formation by the resulting TFO-PBD conjugate occurred more slowly and with a nearly 30-fold lower affinity compared to an unconjugated TFO. PBD binding to the triplex target was demonstrated by protection from restriction enzyme digestion, and covalent binding to the exocyclic amino group of guanine was inferred by substituting specific guanines with inosines. Although the binding of the TFO was less efficient, this report demonstrates that in principle, TFOs can be used to direct the binding of a PBD to specific location. Further optimization of TFO-PBD conjugate design, likely involving optimization of the linker and perhaps placing a PBD at both ends of the TFO, will be needed to make gene modification robust.