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
(520) 626-5622
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
Brahme, N. M., Gonzalez, J. E., Mizsak, S., Rolls, J. R., Hessler, E. J., & Hurley, L. H. (1984). Biosynthesis of the lincomycins. 2. Studies using stable isotopes on the biosynthesis of methylthiolincosaminide moiety of lincomycin A. Journal of the American Chemical Society, 106(25), 7878-7883.

Abstract:

Lincomycin is an antibiotic produced by Streptomyces lincolnensis and consists of a unique aminooctose moiety, α-methylthiolincosaminide (MTL), attached via an amide linkage to a propylhygric acid unit. The biosynthesis of the MTL moiety of lincomycin has been investigated by using both specifically carbon-13 labeled substrates and uniformly carbon-13 labeled D-glucose. In the latter case 13C-13C spin coupling patterns in lincomycin and MTL were used to determine those carbon atoms from glucose that remained intact during their conversion to the antibiotic. By combination of the biosynthetic information obtained from the 13C-13C spin coupling patterns with that from those carbon atoms in MTL which were enriched from carbon-13 specifically labeled molecules, conclusions can be drawn about likely pathways and intermediates between glucose and MTL. The C8-carbon skeleton of MTL is assembled through condensation of a pentose unit (C5) and a C3 unit. The C5 unit can be assembled in two ways. Either it is derived from glucose via the hexose monophosphate shunt (HMPS) as an intact unit or it is assembled from condensation of a C3 unit (glyceraldehyde 3-phosphate) with a C2-unit donor such as sedoheptulose 7-phosphate (SH7P) via a transketolase reaction. The C3 unit, which combines with the C5 unit, is likely contributed from a suitable donor molecule such as SH7P via a transaldolase reaction. Dependent upon the origin of the C3-unit donor, this unit may consist either of an intact C3 unit or a C2 unit combined with a C1 unit. The octase produced from condensation of a C5 unit and a C3 unit can then be converted by unexceptional means to MTL. © 1984 American Chemical Society.

Kshirsagar, T. A., & Hurley, L. H. (1999). Mechanistic insight into the aromatization of cyclic p-quinonemethides to indoles. Heterocycles, 51(1), 185-189.

Abstract:

Two mechanisms have been previously proposed for the aromatization of cyclic p-quinonemethides to indoles. A novel synthetic route to indoles via an unstable cyclic p-quinonemethide has provided additional insight into the mechanism of cyclization. Since this key intermediate lacks the functional groups required for one of the mechanistic pathways (Pathway B), it appears that cyclization occurs via Pathway A.

Armond, R. D., Wood, S., Sun, D., Hurley, L. H., & Ebbinghaus, S. W. (2005). Evidence for the presence of a guanine quadruplex forming region within a polypurine tract of the hypoxia inducible factor 1α promoter. Biochemistry, 44(49), 16341-16350.

PMID: 16331995;Abstract:

The promoter of the hypoxia inducible factor 1 alpha (HIF-1α) gene has a polypurine/polypyrimidine tract (-65 to -85) overlapping or adjacent to several putative transcription factor binding sites, and we found that mutagenesis of this region diminished basal HIF-Iα expression. Oligonucleotides representing this region of the HIF-1α promoter were analyzed by electrophoretic mobility shift, chemical probing, circular dichroism, and DNA polymerase arrest assays. The guanine-rich strand was found to form a parallel, unimolecular quadruplex in the presence of potassium that was further stabilized by two known quadruplex binding compounds, the cationic porphyrin TmPyP4 and the natural product telomestatin, while TmPyP2, a positional isomer of TmPyP4, did not stabilize quadruplex formation. These data suggest that a quadruplex structure may form in a region of the HIF-1α promoter that regulates basal HIF-1α expression. © 2005 American Chemical Society.