Laurence Hurley

Laurence Hurley

Associate Director, BIO5 Institute
Professor, BIO5 Institute
Professor, Medicinal Chemistry-Pharmaceutical Sciences
Professor, Medicinal Chemistry-Pharmacology and Toxicology
Professor, Cancer Biology - GIDP
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

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
Hornemann, U., Speedie, M. K., Kelley, K. M., Hurley, L. H., & Floss, H. G. (1969). Biosynthesis of indoleisopropionic acid by Claviceps. Biological C-methylation involving an intact methyl group. Archives of Biochemistry and Biophysics, 131(2), 430-440.

PMID: 5787216;Abstract:

(R)-Indoleisopropionic acid (I) [(2R)-(3-indolyl)-propionic acid], a metabolite of a Claviceps strain, is formed from l-tryptophan and the intact methyl group of l-methionine. Indoleacetic acid is not incorporated into indoleisopropionic acid. (2R,S), (3S,R)-3-methyltryptophan (β-methyltryptophan, isomer B) was efficiently incorporated, but no evidence for its formation by the organism could be obtained. A hypothetical scheme for the biosynthesis of indoleisopropionic acid is presented. © 1969.

Park, H. -., & Hurley, L. H. (1997). Covalent modification of N3 of guanine by (+)-CC-1065 results in protonation of the cross-strand cytosine. Journal of the American Chemical Society, 119(3), 629-630.
Hurley, L. H., Chandler, C., Garner, T. F., Petrusek, R., & Zimmer, S. G. (1979). DNA binding, induction of unscheduled DNA synthesis, and excision of anthramycin from DNA in normal and repair-deficient human fibroblasts.. Journal of Biological Chemistry, 254(3), 605-608.

PMID: 762084;Abstract:

The reaction of the antitumor antibiotic anthramycin with cellular DNA and the ability of normal human fibroblasts cells and xeroderma pigmentosum (XP) cells to respond to this injury has been evaluated. The binding of [15-3H]anthramycin to cellular DNA in human skin fibroblasts occurred in a linear manner up to 6 h. Treatment with unlabeled antibiotic resulted in unscheduled (repair) DNA synthesis in human skin fibroblasts maintained in hydroxyurea, whereas negligible unscheduled DNA synthesis was observed in cells of an excision-defective strain of XP. Confluent nondividing normal skin fibroblast cells were able to remove 86% of the bound anthramycin within 72 h, however XP cells were only able to remove 49% during the same incubation period. These results are discussed in terms of the types of DNA damage produced by anthramycin in vitro and the likely repair pathways involved in removing lesions produced on DNA by anthramycin.