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

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
Petrusek, R. L., Uhlenhopp, E. L., Duteau, N., & Hurley, L. H. (1982). Reaction of anthramycin with DNA. Biological consequences of DNA damage in normal and xeroderma pigmentosum cell lines. Journal of Biological Chemistry, 257(11), 6207-6216.

PMID: 7076670;Abstract:

Anthramycin, an antitumor antibiotic produced by Streptomyces refuineus, produces a well defined covalent adduct with DNA and lies within the narrow groove of DNA, attached through a thermal-labile covalent aminal linkage to the exocyclic amino group of guanine, without detectable distortion of the helix. This paper describes results in which the biological consequences of DNA damage and repair by repair-proficient and a repair-deficient xeroderma pigmentosum (XP 12RO) cell line are presented. Anthramycin has been shown to produce excision-dependent single and double strand breaks in DNA, both of which appear to persist many hours after removal of the drug from the media. The lower ability of the xeroderma pigmentosum cell line to remove anthramycin lesions from DNA is correlated with a decreased cell survival. The biological consequences of DNA damage (genetic effects, DNA strand breakage, and cytotoxicity) are discussed with respect to the defined structure and stability of the anthramycin-deoxyguanosine adduct.

Hurley, L., Carey, S. S., Gleason-Guzman, M., Gokhale, V., & Hurley, L. -. (2008). Psorospermin structural requirements for P-glycoprotein resistance reversal. Molecular cancer therapeutics, 7(11).

Resistance to chemotherapy reduces its effectiveness, resulting in increased mortality. Psorospermin, a natural product, is a topoisomerase II-directed DNA alkylating agent active against multidrug-resistant (MDR) cell lines, including multiple myeloma. In this study, the mechanism of the P-glycoprotein (P-gp) modulation activity of psorospermin and that of its associated pharmacophore were examined. Flow cytometry shows that doxorubicin-resistant multiple myeloma cells (8226/D40) pretreated with psorospermin enhance intracellular retention of doxorubicin compared with control (75% versus 38%). Because the overexpression of P-gp is the primary cause of drug resistance in the 8226/D40 cells, psorospermin-induced sensitization was likely due to mdr1/P-gp expressional or functional inhibition. As shown by PCR and Western blot, neither transcription of mdr1 nor translation of P-gp was down-regulated by psorospermin treatment. Therefore, the mechanism of psorospermin-induced resistance reversal is most likely through a direct interaction between psorospermin and P-gp. Furthermore, because only the (2'R,3'R) isomer of psorospermin showed any resistance reversal activity, the side chain of psorospermin is apparently a crucial moiety for resistance reversal. By understanding the mechanism of psorospermin-induced MDR modulation, psorospermin and similar compounds can be combined with other chemotherapies to treat resistant cancers.

Hurley, L. H., Lee, C., McGovren, J. P., Warpehoski, M. A., Mitchell, M. A., Kelly, R. C., & Aristoff, P. A. (1988). Molecular basis for sequence-specific DNA alkylation by CC-1065. Biochemistry, 27(10), 3886-3892.

PMID: 3408734;Abstract:

CC-1065 is a potent antitumor antibiotic that binds covalently to N3 of adenine in the minor groove of DNA. The CC-1065 molecule is made up of three repeating pyrroloindole subunits, one of which (the left-hand one or A subunit) contains a reactive cyclopropyl function. The drug reacts with adenines in DNA in a highly sequence-specific manner, overlapping four base pairs to the 5′-side of the covalently modified base. Concomitant with CC-1065 covalent binding to DNA is an asymmetric effect on local DNA structure which extends more than one helix turn to the 5′-side of the covalent binding site. The DNA alkylation, sequence specificity, and biological potency of CC-1065 and a select group of trimeric synthetic analogues were evaluated. The results suggest that (a) noncovalent interactions between this series of compounds and DNA do not lead to the formation of complexes stable enough to be detected by footprinting methods, (b) sequence specificity and alkylation intensity can be modulated by the substituents on the nonreactive middle and right-hand segments, and (c) biological potency correlates well with ability to alkylate DNA. In addition, the extent and the sequence specificity of covalent adduct formation between linear DNA fragments and three analogues comprised of the CC-1065 alkylating subunit linked to zero (analogue A), one (analogue AB), or two (analogue ABC) nonreactive indole subunits were compared. The results suggest that specificity of covalent binding of this analogue series is controlled not by the noncovalent interactions of the B and C subunits with the minor groove but by sequence-dependent reactivity of adenines with the alkylating (A) subunit. However, the B and C subunits markedly increase the apparent rate constant of the reaction with "susceptible" adenines, suggesting that these moieties facilitate noncovalent interactions preceding covalent bond formation. Covalent binding of the analogue consisting only of the alkylating subunit of CC-1065 (analogue A) was associated with the same large asymmetric effect on DNA structure as the entire CC-1065 molecule. This altered local DNA structure could be a consequence of adduct formation. Alternatively, it may be indirect evidence of a particular DNA conformation which existed prior to covalent bond formation and which was "trapped" by the drug. It is proposed that certain adenine-containing sequences have an increased propensity to undergo such a local conformational change and that this is the molecular basis for sequence specificity of these DNA-reactive compounds. These results provide strong experimental evidence for the importance of sequence-dependent site reactivity, rather than noncovalent minor groove interactions, in determining the alkylation specificity of some DNA-reactive molecules. © 1988 American Chemical Society.