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

Lin, C. H., Beale, J. M., & Hurley, L. H. (1991). Structure of the (+)-CC-1065-DNA adduct: Critical role of ordered water molecules and implications for involvement of phosphate catalysis in the covalent reaction. Biochemistry, 30(15), 3597-3602.

PMID: 2015216;Abstract:

(+)-CC-1065 is an extremely potent antitumor agent produced by Streptomyces zelensis. The potent effects of (+)-CC-1065 and its alkylating analogues are thought to be due to the formation of a covalent adduct through N3 of adenine in DNA. It has been previously postulated, on the basis of modeling studies, that a phosphate may be involved in stabilization of the adduct and in acid catalysis of this reaction. In this study, using 1H NMR in combination with 17O-labeled water and phosphate, we demonstrate the involvement of a bridging water molecule between a phenolic proton on the alkylating subunit of (+)-CC-1065 and an anionic oxygen in the phosphate on the noncovalently modified strand of DNA. In addition, a second ordered water molecule associated with one of the protons on N6 of the covalently modified adenine is also identified. This structure has important implications for catalytic activation of the covalent reaction between (+)-CC-1065 and DNA and, consequently, the molecular basis for sequence-selective recognition of DNA by the alkylating subunit of (+)-CC-1065. On the basis of the example described here, the use of 1H NMR in 17O-labeled water may be a powerful probe to examine other structures and catalytic processes for water-mediated hydrogen-bonded bridges that occur between small molecules and DNA or enzymes. © 1991 American Chemical Society.

Dallam, R. A., Lubawy, W. C., & Hurley, L. H. (1979). Pyrrolo(1,4)benzodiazepine antitumor antibiotics. Combined protective therapy with co-enzyme Q10 or vitamin E and the antitumor antibiotic anthramycin. Journal of Natural Products, 42(6), 693-.
Ostrander, J. M., Hurley, L. H., Balakrishnan, M. S., & Krugh, T. (1981). Determination of the structure of the anthramycin-DNA adduct by 1H and 13C-NMR spectroscopy. Journal of Supramolecular and Cellular Biochemistry, 15(Suppl.5), No. 446.
Sun, D., & Hurley, L. H. (1994). Binding of Sp1 to the 21-bp repeat region of SV40 DNA: effect of intrinsic and drug-induced DNA bending between GC boxes. Gene, 149(1), 165-172.

PMID: 7958981;Abstract:

The effect of the antitumor antibiotic (+)-CC-1065 on the binding of Spl to the 21-bp repeats of SV40 DNA has been investigated. (+)-CC-1065 alkylates N3 of adenine in DNA and resides in the minor groove. As a consequence of alkylation of the two 5prime;-AGTTA* sequences (* indicates covalent modification site), which reside between GC boxes III and IV, and boxes V and VI, protein binding to the 3prime; sites is completely abolished and there is a significant decrease in Sp1 binding to the other regions. The effect of substituting A5 tracts for the (+)-CC-1065-bonding sequence was intermediate between the unmodified 5prime;-AGTTA* and the drug-modified sequences. It is proposed that a structural distortion of DNA associated with stiffening of the helix induced by the drug-adduct formation is primarily responsible for the inhibition of binding of Spl molecules to 21-bp repeats, rather than steric hindrance due to the occupancy by drug molecules of the minor groove within that region. © 1994.

Find Us On

youtube

Stay Connected

Subscribe to our newsletter