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

Hurley, L. H. (1976). Pyrrolo[1,4]benzodiazepine antibiotics. Biosynthesis of the antitumor antibiotic 11-demethyltomaymycin and its biologically inactive metabolite oxotomaymycin by streptomyces achromogenes. Biochemistry, 15(17), 3760-3769.

PMID: 1085163;Abstract:

11-Demethyltomaymycin, an antitumor antibiotic produced by Streptomyces achromogenes, and its biologically inactive metabolite oxotomaymycin are biosynthesized from L-tyrosine, DL-tryptophan, and L-methionine. The anthranilate part of 11-demethyltomaymycin is derived from tryptophan probably via the kynurenine pathway. The predominant loss of tritium from DL-[5-3H]tryptophan, during its conversion to 11-demethyltomaymycin and oxotomaymycin is interpreted to mean by NIH shift rules, that the main pathway to the 5-methoxy-4-hydroxy anthranilate moiety is through hydroxylation at C-8 prior to hydroxylation at C-7. The methoxy carbon is derived from the S-methyl group of methionine by transfer of an intact methyl group. The ethylideneproline moiety of 11-demethyltomaymycin is biosynthesized from tyrosine, without a 1-carbon unit from methionine. The results of biosynthetic feeding experiments with L-[1-14C, 3- or 5-3H] tyrosine are consistent with a "meta" or extradiol cleavage of 6, 7-dihydroxycyclodopa as has also been demonstrated previously for anthramycin and lincomycin A. An experiment in which L-[1-14C, Ala-2,3-3H]tyrosine was fed showed that both of the β hydrogens of this amino acid are retained in 11-demethyltomaymycin. It has been demonstrated in cultures and washed cell preparations that 11-demethyltomaymycin is enzymatically converted to oxotomaymycin by an intracellular constitutive enzyme. Conversion of oxotomaymycin to 11-demethyltomaymycin by these same preparations could not be demonstrated. The enzymatic activity associated with the conversion of 11 -demethyltomaymycin to oxotomaymycin is not limited to the 11-demethyltomaymycin production phase, since trophophase cells and even cells from 11-demethyltomaymycin nonproducing cultures of S. achromogenes were equally active in converting 11-demethyltomaymycin to oxotomaymycin.

Hurley, L. H. (2002). DNA and its associated processes as targets for cancer therapy. Nature Reviews Cancer, 2(3), 188-200.

PMID: 11990855;Abstract:

DNA is the molecular target for many of the drugs that are used in cancer therapeutics, and is viewed as a non-specific target of cytotoxic agents. Although this is true for traditional chemotherapeutics, other agents that were discovered more recently have shown enhanced efficacy. Furthermore, a new generation of agents that target DNA-associated processes are anticipated to be far more specific and effective. How have these agents evolved, and what are their molecular targets?

Hurley, L. H., D., D., Siddiqui-Jain, A., & Yang, D. (2006). Drug Targeting of the c-MYC Promoter to Repress Gene Expression via a G-Quadruplex Silencer Element. Seminars in Oncology, 33(4), 498-512.

PMID: 16890804;Abstract:

In this review, we describe the evidence for a parallel-stranded G-quadruplex in the purine-rich strand of the nuclease hypersensitivity element III1 (NHE III1) of the promoter of c-MYC upstream of the P1 and P2 promoters. This biologically relevant G-quadruplex is a mixture of four loop isomers. The folding pattern of a nuclear magnetic resonance (NMR)-derived structure for the predominant loop isomer of this G-quadruplex has been obtained. This G-quadruplex has been demonstrated to be a silencer element, and the cationic porphyrin TMPyP4 has been shown to stabilize this G-quadruplex. Furthermore, TMPyP4 has been shown to repress c-MYC expression, and this effect is mediated through the silencer element. Last, the in vivo activity of TMPyP4 in xenograph models is presented. © 2006 Elsevier Inc. All rights reserved.

Hansen, M., Lee, S., Cassady, J. M., & Hurley, L. H. (1996). Molecular details of the structure of a psorospermin - DNA covalent/intercalation complex and associated DNA sequence selectivity. Journal of the American Chemical Society, 118(24), 5553-5561.

Abstract:

Psorospermin is a DNA-reactive natural product isolated from the roots of the tropical African plant Psorospermum febrifugum that shows significant promise as an antileukemic agent. Incubation of this antineoplastic agent with DNA results in the production of sequence selective abasic sites on the DNA. Using high-field NMR and gel electrophoresis, the mechanism of covalent modification of DNA and the mode of interaction with DNA are determined. Psorospermin intercalates the DNA molecule, positioning the tricyclic xanthone chromophore in an orientation parallel to the adjacent base pairs. This places the epoxide in the major groove, resulting in site-directed electrophilic addition of the epoxide to N7 of guanine located to the 3' side of the site of DNA intercalation. It is proposed in this study that the subsequent depurination of the psorospermin - N7-guanine adduct is the source of the previously observed in vivo formation of abasic sites on the DNA. Significantly, although the chemical structure and mechanism of covalent modification of DNA are very similar to those of the pluramycin class of agents, there are distinct differences in the relative reactivities and sequence selectivity between psorospermin and pluramycin-like compounds that may give rise to observed variances in biological activity. Specifically, while psorospermin is much less reactive than most of the pluramycins, it shows unique selectivity for 5'GG* sequences (the asterisk designates the site of covalent modification), which is the least reactive site for all of the pluramycins investigated thus far. On the basis of the solution NMR structure of the psorospermin - DNA covalent adduct, the underlying structural differences that give rise to this lower reactivity and different sequence specificities are proposed.

Liang, W. S., Hendricks, W., Kiefer, J., Schmidt, J., Sekar, S., Carpten, J., Craig, D. W., Adkins, J., Cuyugan, L., Manojlovic, Z., Halperin, R. F., Helland, A., Nasser, S., Legendre, C., Hurley, L. H., Sivaprakasam, K., Johnson, D. B., Crandall, H., Busam, K. J., , Zismann, V., et al. (2017). Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma. Genome research, 27(4), 524-532.

Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. In contrast with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of TERT in ALM tumorigenesis and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM.

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