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

Palumbo, S. L., Memmott, R. M., Uribe, D. J., Krotova-Khan, Y., Hurley, L. H., & Ebbinghaus, S. W. (2008). A novel G-quadruplex-forming GGA repeat region in the c-myb promoter is a critical regulator of promoter activity. Nucleic Acids Research, 36(6), 1755-1769.

PMID: 18252774;PMCID: PMC2330228;Abstract:

The c-myb promoter contains multiple GGA repeats beginning 17 bp downstream of the transcription initiation site. GGA repeats have been previously shown to form unusual DNA structures in solution. Results from chemical footprinting, circular dichroism and RNA and DNA polymerase arrest assays on oligonucleotides representing the GGA repeat region of the c-myb promoter demonstrate that the element is able to form tetrad:heptad:heptad:tetrad (T:H:H:T) G-quadruplex structures by stacking two tetrad:heptad G-quadruplexes formed by two of the three (GGA)4 repeats. Deletion of one or two (GGA)4 motifs destabilizes this secondary structure and increases c-myb promoter activity, indicating that the G-quadruplexes formed in the c-myb GGA repeat region may act as a negative regulator of the c-myb promoter. Complete deletion of the c-myb GGA repeat region abolishes c-myb promoter activity, indicating dual roles of the c-myb GGA repeat element as both a transcriptional repressor and an activator. Furthermore, we demonstrated that Myc-associated zinc finger protein (MAZ) represses c-myb promoter activity and binds to the c-myb T:H:H:T G-quadruplexes. Our findings show that the T:H:H:T G-quadruplex-forming region in the c-myb promoter is a critical cis-acting element and may repress c-myb promoter activity through MAZ interaction with G-quadruplexes in the c-myb promoter. © 2008 The Author(s).

Hurley, L., Yang, D., & Hurley, L. -. (2006). Structure of the biologically relevant G-quadruplex in the c-MYC promoter. Nucleosides, nucleotides & nucleic acids, 25(8).

The nuclease hypersensitivity element III1 (NHE III1) in the c-MYC promoter controls up to 80-90% of the transcriptional activity of this gene. We have demonstrated that the guanine-rich strand of the NHE III1 forms a G-quadruplex consisting of a mixture of four biologically relevant loop isomers that function as a silencer element. NMR studies have shown that these G-quadruplexes are propeller-type parallel structures consisting of three stacked G-tetrads and three double-chain reversal loops. An NMR-derived solution structure for this quadruplex provides insight into the unusual stability of the structure. This structure is a target for small molecule inhibitors of c-MYC gene expression.

Weldon, C., Dacanay, J. G., Gokhale, V., Boddupally, P. V., Behm-Ansmant, I., Burley, G. A., Branlant, C., Hurley, L. H., Dominguez, C., & Eperon, I. C. (2018). Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X. Nucleic acids research, 46(2), 886-896.

Sequences with the potential to form RNA G-quadruplexes (G4s) are common in mammalian introns, especially in the proximity of the 5' splice site (5'SS). However, the difficulty of demonstrating that G4s form in pre-mRNA in functional conditions has meant that little is known about their effects or mechanisms of action. We have shown previously that two G4s form in Bcl-X pre-mRNA, one close to each of the two alternative 5'SS. If these G4s affect splicing but are in competition with other RNA structures or RNA binding proteins, then ligands that stabilize them would increase the proportion of Bcl-X pre-mRNA molecules in which either or both G4s had formed, shifting Bcl-X splicing. We show here that a restricted set of G4 ligands do affect splicing, that their activity and specificity are strongly dependent on their structures and that they act independently at the two splice sites. One of the ligands, the ellipticine GQC-05, antagonizes the major 5'SS that expresses the anti-apoptotic isoform of Bcl-X and activates the alternative 5'SS that expresses a pro-apoptotic isoform. We propose mechanisms that would account for these see-saw effects and suggest that these effects contribute to the ability of GQC-05 to induce apoptosis.

Hornemann, U., Speedie, M. K., Hurley, L. H., & Floss, H. G. (1970). Demonstration of a C-methylating enzyme in cell free extracts of indolmycin-producing Streptomycesgriseus. Biochemical and Biophysical Research Communications, 39(4), 594-599.

PMID: 5490210;Abstract:

A cell free extract of an indolmycin-producing strain of Streptomycesgriseus is shown to catalyze the transfer of a methyl group from S-adenosylmethionine-(methyl-14C) to indolepyruvate to form radioactive β-methylindolepyruvate, an intermediate in indolmycin biosynthesis. The reaction product β-methylindolepyruvate has been unequivocally identified by chemical correlations and it has been shown to have the S configuration. © 1970.

Petrusek, R. L., Anderson, G. L., Garner, T. F., Fannin, Q. L., Kaplan, D. J., Zimmer, S. G., & Hurley, L. H. (1981). Pyrrolo[1,4]benzodiazepine antibiotics. Proposed structures and characteristics of the in vitro deoxyribonucleic acid adducts of anthramycin, tomaymycin, sibiromycin, and neothramycins A and B. Biochemistry, 20(5), 1111-1119.

PMID: 6261786;Abstract:

The pyrrolo[1,4]benzodiazepine antibiotics anthramycin, tomaymycin, sibiromycin, and neothramycins A and B are potent antitumor agents that bind to DNA in a unique manner, resulting in some unusual biological consequences. This paper describes results on which the points of covalent linkage between the drugs (carbinolamine carbon atom) and DNA (N-2 of guanine) are deduced, as well as Corey-Pauling-Koltun (CPK) models for the various drug-DNA adducts. Predictions based upon these CPK models have been tested, and the results are reported in this paper. These tested experimental predictions include (1) instability of the drug-DNA adducts to denaturation of DNA, (2) saturation binding limits, (3) effect of drug binding on the structure of DNA, (4) lack of unwinding and in vitro strand breakage of closed-circular supercoiled simian virus 40 (SV-40) DNA, (5) sensitivity of the secondary structure of DNA to drug binding, (6) hydrodynamic properties of the drug-DNA adducts, (7) hydrogen bonding of the 9-phenolic proton in anthramycin to DNA, (8) structure-activity relationships, and (9) biological consequences of DNA damage, including cumulative damage and slow excision repair, double-strand breaks in DNA in repair-proficient cells, and the selective inhibition of H-strand DNA synthesis in mitochondria. The results are completely in accord with our postulated space-filling models. © 1981 American Chemical Society.

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