Laurence Hurley, PhD

Professor Emeritus, Medicinal Chemistry
CSO, Reglagene LLC

Laurence Hurley, PhD, professor emeritus, College of Pharmacy Drug Discovery and Development, specializes in the design and development of antitumor agents. He started three biotech companies and presently serves as CEO of Reglagene, LLC, which develops small-molecule medicines to fight disease.

Hurley has published extensively in the area of chemical biology, most recently about targeting transcriptional control through quadruplexes. Named 2017 Arizona Bioscience Researcher of the Year and inducted into the 2007 American Chemical Society Medicinal Chemistry Division Hall of Fame, he received the George and Christine Sosnovsky Award in Cancer Therapy by the ROYAL SOCIETY OF Chemistry among others. He has been awarded DSc degrees from Purdue University and the University of Bath (UK).

Education & Post Graduate Training: 

Post-Doctoral Fellow, Chemistry Department, University of British Columbia (Canada), 1972
PhD, Medicinal Chemistry, Purdue University (Indiana), 1970
BPharm, Pharmacy with Honors, Bath University (England), 1967

Clinical Expertise: 

In 2006 Quarfloxin entered phase 1 clinical trials. This drug originated from QQ58, a compound synthesized in the Hurley laboratory at The University of Texas at Austin (Duan et al. [2001] Mol. Cancer Ther., 1, 103), which was subsequently developed at Cyternex/Cylene Pharmaceuticals in San Diego while Hurley was scientific founder and CSO (1997–2006).

Research Summary: 

Dr. Hurley’s present research interests are in the areas of design and development of antitumor agents. Over the last forty years, work from his laboratory has led to elucidation of the structures of the drug–nucleic acid complexes for seven different groups of compounds that are potentially useful in the treatment of cancer. In cooperation with the pharmaceutical industry, several drugs developed with the aid of these studies have been evaluated in phase 1 and 2 clinical trials. Most recently his research has centered on secondary DNA structures, particularly G-quadruplexes and C-quadruplexes (also called i-motifs), as gene targets for drug design. While he was CSO of Cylene Pharmaceuticals a first-in-class G-quadruplex-interactive compound (Quarfloxin), developed from this technology and licensed from the University of Arizona, was advanced into phase 1 and 2 clinical trials in 2007.

Areas of Research: 
Discovery and Development of Quarfloxin, the First-in-Class G-Quadruplex-Interactive Agent (1997–2006)

G-quadruplexes had only been suggested as potential noncanonical DNA structures that might have some biological roles up to the late 1990s, but there was no solid evidence that they existed in cells and the biological community was very skeptical. This skepticism was increased because Z-DNA had been proposed to have important biological roles; but despite considerable investment, no such role had been demonstrated. It was in this scientific atmosphere that we set out as medicinal chemists to work on developing G-quadruplexes as drug targets. We were the first to propose that G-quadruplexes could be selective targets for drug design (Hurley [1989] J. Med. Chem., 32, 2027) and to demonstrate that telomeric G-quadruplexes (Sun et al. [1997] J. Med. Chem., 40, 2113) and then promoter G-quadruplexes (MYC) (Siddiqui-Jain et al. [2002] Proc. Natl. Acad. Sci. U.S.A., 99, 11593) could be targeted by small molecules. In 2006 Quarfloxin entered phase 1 clinical trials. This drug originated from QQ58, a compound synthesized in our laboratory at UT Austin (Duan et al. [2001] Mol. Cancer Ther., 1, 103), which was subsequently developed at Cyternex/Cylene Pharmaceuticals in San Diego while I was scientific founder and CSO (1997–2006). 

Validation of the Role of G-Quadruplexes and i-Motifs as Silencer and Activation Elements in Core Promoter Sequences (2008–present)

The high enrichment of putative G-quadruplex- and i-motif-forming sequences upstream of the transcription start site in core promoter elements suggested a role for these structures in controlling gene expression. In pioneering studies the Levens lab at NCI had demonstrated that transcriptionally induced negative superhelicity can provide the energy to induce the formation of noncanonical DNA structures far upstream of the MYC promoter. Following these studies we have shown that the formation of G-quadruplexes and i-motifs require both negative superhelicity and the wild-type sequence to form these structures (Sun and Hurley [2009] J. Med. Chem., 52, 2863). We were then the first to identify transcription factors that bound to promoter G-quadruplexes and i-motifs to either silence or activate gene transcription (González et al. [2009] J. Biol. Chem., 284, 23622; Kang et al. [2014] J. Am. Chem. Soc., 136, 4172).  In recent work (Song et al. [2018] Cell Chem. Biol., 26, 1110) we have shown that we can specifically target the hairpin loop of the hTERT promoter G-quadruplex to induce cancer cell death.

Demonstration That i-Motifs in Promoter Elements Can Be Validated as Drug Targets (2009–present)

Since persuading the scientific community that G-quadruplexes were biologically relevant, we were not surprised to find that convincing the same community of the relevancy of i-motifs was even more of a challenge, since while G-quadruplexes are stable under physiological conditions, the stability of the i-motif in a test tube requires an acidic pH. This skepticism is valid unless one also takes into account the effect of stabilizing loop sequences (Kendrick et al. [2009] J. Am. Chem. Soc., 131, 17667) and the effect of torsional stress induced by transcriptionally induced negative superhelicity (Sun and Hurley [2009] J. Med. Chem., 52, 2863). To convince the community that i-motifs are both valid drug targets and dynamically accessible, we published back-to-back papers in the Journal of the American Chemical Society that demonstrate that the BCL2 i-motif and its equilibrating unfolded heteroduplex can be targeted by different steroids to either downregulate or upregulate gene transcription, thus showing for the first time that i-motifs can act as molecular switches in DNA (Kendrick et al [2014] J. Am. Chem. Soc., 136, 4161). It is the dynamic character of the BCL2 promoter i-motif that provides this mechanism for modulation of gene expression by compounds that change the population equilibrium by binding selectively to the i-motif or the heteroduplex species (Kendrick et al [2014] J. Am. Chem. Soc., 136, 4161). We also demonstrated that the transcriptional factor hnRNP LL recognizes the BCL2 i-motif and unfolds it to form a transcriptionally activated species and that the occupancy of this protein at the BCL2 promoter element is modulated by the two different steroids (Kang et al. [2014] J. Am. Chem. Soc., 136, 4172). Collectively this work demonstrates that the transcription complex between the BCL2 i-motif and hnRNP LL is a molecular switch for the control of gene expression that can be modulated by small molecules to modulate gene expression. 

Molecular Basis for the Duplex DNA Sequence Selectivity for Covalent Bonding Drugs (1979–1991)

In the late 1970s little was known about how DNA-reactive compounds recognized and then bound covalently to DNA. In papers published in Nature and Science in 1979 and 1984, we demonstrated for the first time the DNA sequence selectivity and mechanism for covalent modification of guanine and adenine in duplex DNA (Hurley and Petrusek [1979] Nature, 282, 529; Hurley et al. [1984] Science, 226, 843). The structures of these drug–DNA complexes led to the development of clinical-stage drugs from both of these groups of compounds and other DNA covalent bonding agents where we characterized the structures of the drug–DNA adduct structures (Adozelesin, Bizelesin, Yondelis, and SJG-136). Some of these same drugs are now being used as the warheads in ADC therapeutics (SGN-CD33A). 

Biosynthesis of Antitumor Agents and Antibiotics (1971–1981)

Following my graduate and postdoctoral studies in natural products chemistry in the late 1960s/early 1970s, the use of both radioactive and stable isotope techniques to elucidate the building blocks and biosynthetic pathways was state of the art. Our biosynthetic studies, which required synthetic chemistry, NMR, and antibiotic fermentation studies on the antitumor antibiotics belonging to the pyrrolobenzodiazepine (anthramycin) and cyclopropylindole (CC-1065) series, led us to identify the biosynthetic building blocks and propose pathways for their bio-genesis (Hurley (1977) J. Antibiot., 30, 349; Hurley (1980) Acc. Chem. Res., 13, 263). In addition, the specifically labeled species produced as a consequence of these studies laid the foundation for our mechanism of action studies described above, and thus our transition from natural products chemistry to chemical biology when molecular biology was still a distant horizon for most practicing medicinal chemist in academia and industry. In 1987 I wrote an invited editorial for J. Med. Chem. titled “Molecular biology and medicinal chemistry” (October, vol. 30, no. 10, p. 7A) that was well received by the medicinal chemistry community

Types of Research: 
Clinical Trials
Laboratory-based Research
Literature Reviews
Professional Organizations: 
  • American Chemical Society (current)
  • American Association for Cancer Research (current) 
  • Rho Chi Pharmacy Honor Society (current) 
  • Phi Kappa Phi Honor Society (current) 
  • American Association for the Advancement of Science (current) 
  • American Association of Colleges of Pharmacy (current) 
  • Chemical Society of Great Britain 
  • American Society for Microbiologists 
  • Academy of Pharmaceutical Sciences

Editorial Offices​​:

  • Journal of Medicinal Chemistry (Senior Editor) (1992–2010) 
  • Current Medicinal Chemistry (Associate Editor) (2001–2010)
  • Advances in DNA Sequence Specific Agents (General Editor) (1991–1997) 
  • Anti-Cancer Drug Design (U.S. Editor) (1991–1992) 

Editorial Boards:

  • International Journal of Oncology (2005–2015)
  • Molecular Cancer Therapeutics (2001–2010)
  • Journal of New Anticancer Agents (1989–1991)
  • Chemical Research in Toxicology (1989–1992)
  • Pharmacological and Pharmaceutical Letters (1991–1992) 

NIH/NCI Program and Grant Review Responsibilities:

  • 2015 Site Visit and Review, David Levens Lab, NCI
  • 2010–2011 Chair, Board of Scientific Councilors, NCI
  • 2007–2010 Member, Board of Scientific Councilors, NCI
  • 1992 Chairman, NCI Special Study Section for Outstanding Investigator Grant
  • 1988–1992 NIH Bioorganic and National Products Chemistry Study Section reserve board
  • 1986–1988 Chairman, NIH Bioorganic and Natural Products Chemistry Study Section
  • 1984–1986 NIH Bioorganic and Natural Products Chemistry Study Section Member 

Scientific Advisory Boards:

  • 2013–2017 International Representative, NRN Management Board, Life Sciences Research Network, Cardiff, Wales
  • 2006–2014 University of Minnesota Cancer Center External Scientific Advisory Board
  • 2006–2014 University of Minnesota Center for Drug Discovery External Advisory Board
  • 2006–2010 Purdue Cancer Center External Advisory Board
  • 2004 Chair, External Advisory Board, Experimental Therapeutics Program, University of Minnesota
  • 1997–1998 SunPharm
  • 1997–2006 Cylene Pharmaceuticals, Chair and CSO
  • 1990–2000 Institute for Drug Development, San Antonio 

Consultantships:

  • Hoffmann-La Roche, Basel (1989–1992) 
  • Abbott Laboratories, Chicago (1990–1994) 
  • Review of Graduate and Professional Program, Kumamoto University, Japan (1999) 
  • Consultant, University of Kentucky Cancer Center (1984) 
  • Consultant to Smith, Kline and Beckman Company (1983–1986) 
  • Consultant to the Upjohn Company (1977–1992)

Select Publications

2019

Song, J. H., H-J. Kang, L. A. Luevano, V. Gokhale, K. Wu, R. Pandey, H-H. Sherry Chow, L. H. Hurley, and A. S. Kraft, "Small-Molecule-Targeting Hairpin Loop of hTERT Promoter G-Quadruplex Induces Cancer Cell Death", Cell Chem Biol, vol. 26, pp. 1110–1121, 2019. PMID: 31155510

2018

Ho, D., J. A. Kretzmann, M. Norret, P. Toshniwal, J-P. Veder, H. Jiang, P. Guagliardo, A. M. Munshi, R. Chawla, C. W. Evans, et al., "Intracellular speciation of gold nanorods alters the conformational dynamics of genomic DNA", Nat Nanotechnol, vol. 13, pp. 1148–1153, 2018.

2017

Kaiser, C. E., N. A. Van Ert, P. Agrawal, R. Chawla, D. Yang, and L. H. Hurley, "Insight into the Complexity of the i-Motif and G-Quadruplex DNA Structures Formed in the KRAS Promoter and Subsequent Drug-Induced Gene Repression.", J Am Chem Soc, vol. 139, issue 25, pp. 8522-8536, 2017 06 28. PMCID: PMC5978000  PMID: 28570076

2016

Sutherland, C., Y. Cui, H. Mao, and L. H. Hurley, "A Mechanosensor Mechanism Controls the G-Quadruplex/i-Motif Molecular Switch in the MYC Promoter NHE III1.", J Am Chem Soc, vol. 138, pp. 14138–14151, 2016.

2011

Balasubramanian, S., L. H. Hurley, and S. Neidle, "Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?", Nat Rev Drug Discov, vol. 10, issue 4, pp. 261-75, 2011 Apr. PMCID: PMC3119469  PMID: 21455236

2002

Kim, M-Y., H. Vankayalapati, K. Shin-Ya, K. Wierzba, and L. H. Hurley, "Telomestatin, a potent telomerase inhibitor that interacts quite specifically with the human telomeric intramolecular g-quadruplex.", J Am Chem Soc, vol. 124, issue 10, pp. 2098-9, 2002 Mar 13. PMID: 11878947
Siddiqui-Jain, A., C. L. Grand, D. J. Bearss, and L. H. Hurley, "Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription.", Proc Natl Acad Sci U S A, vol. 99, issue 18, pp. 11593-8, 2002 Sep 03. PMCID: PMC129314 
Hurley, L. H., "DNA and its associated processes as targets for cancer therapy.", Nat Rev Cancer, vol. 2, issue 3, pp. 188-200, 2002 Mar.

1997

Sun, D., B. Thompson, B. E. Cathers, M. Salazar, S. M. Kerwin, J. O. Trent, T. C. Jenkins, S. Neidle, and L. H. Hurley, "Inhibition of human telomerase by a G-quadruplex-interactive compound.", J Med Chem, vol. 40, issue 14, pp. 2113-6, 1997 Jul 04. PMID: 9216827