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

Zewail-Foote, M., & Hurley, L. H. (1999). Molecular approaches to achieving control of gene expression by drug intervention at the transcriptional level. Anti-Cancer Drug Design, 14(1), 1-9.

PMID: 10363023;Abstract:

In this article we first very briefly review current approaches to the design of drugs that have specificity for the modulation of gene expression and selectivity for target cells at the transcription level by targeting DNA. We focus this review on our approaches to gaining selectivity by drug-induced architectural alteration in DNA structure, selectivity achieved by protein-induced changes in DNA structure or dynamics, and hijacking of nuclear receptors.

Zhou, Q., Duan, W., Simmons, D., Shayo, Y., Raymond, M. A., Dorr, R. T., & Hurley, L. H. (2001). Design and synthesis of a novel DNA-DNA interstrand adenine-guanine cross-linking agent [1]. Journal of the American Chemical Society, 123(20), 4865-4866.
Tang, M., Nazimiec, M. E., Doisy, R. P., Pierce, J. R., Hurley, L. H., & Alderete, B. E. (1991). Repair of Helix-stabilizing anthramycin-N2 guanine DNA adducts by UVRA and UVRB proteins. Journal of Molecular Biology, 220(4), 855-866.

PMID: 1831859;Abstract:

The transfectivity of anthramycin (Atm)-modified φX174 replicative form (RF) DNA in Escherichia coli is lower in uvrA and uvrB mutant cells but much higher in uvrC mutant cells compared to wild-type cells. Pretreatment of the Atm-modified phage DNA with purified UVRA and UVRB significantly increases the transfectivity of the DNA in uvrA or uvrB mutant cells. This pretreatment greatly reduces the UVRABC nuclease-sensitive sites (UNSS) and Atm-induced absorbance at 343 nm in the Atm-modified DNA without producing apurinic sites. The reduction of UNSS is proportional to the concentrations of UVRA and UVRB and the enzyme-DNA incubation time and requires ATP. We conclude that there are two different mechanisms for repairing Atm-N2 guanine adducts by UVR proteins: (1) UVRA and UVRB bind to the Atm-N2 guanine double-stranded DNA region and consequently release the Atm from the adducted guanine; (2) UVRABC makes an incision at both sides of the Atm-DNA adduct. The latter mechanism produces potentially lethal double-strand DNA breaks in Atm-modified φX174 RF DNA in vitro. © 1991 Academic Press Limited.

Weldon, C., Behm-Ansmant, I., Hurley, L. H., Burley, G. A., Branlant, C., Eperon, I. C., & Dominguez, C. (2016). Identification of G-quadruplexes in long functional RNAs using 7-deazaguanine RNA. Nature chemical biology, 13(1), 18-20.

RNA G-quadruplex (G4) structures are thought to affect biological processes, including translation and pre-mRNA splicing, but it is not possible at present to demonstrate that they form naturally at specific sequences in long functional RNA molecules. We developed a new strategy, footprinting of long 7-deazaguanine-substituted RNAs (FOLDeR), that allows the formation of G4s to be confirmed in long RNAs and under functional conditions.

Find Us On

youtube

Stay Connected

Subscribe to our newsletter