Danzhou Yang, PhD
Associate Professor;
Associate Professor, Department of Chemistry;
Comprehensive Member, Arizona Cancer Center;
Member, BIO5 Institute;
Director, College of Pharmacy NMR Facility
Department:
Pharmacology and Toxicology
(520) 626-5969
Fax:
(520) 626-2466
E-mail:
Location:
Pharmacy 406
Bio / Research:
Cancer-specific molecular targets have become a frontier of new anticancer drug development. Research in my laboratory is focused on structural and mechanistic studies of cancer-specific molecular targets and their interactions with small molecule compounds for structure-based rational drug design. My research program involves the implementation of a variety of biophysical and biochemical methods, in particular high-field NMR spectroscopy. We work on a number of molecular targets for cancer therapeutic intervention, including the DNA G-quadruplex secondary structures formed in the oncogene promoter regions and in human telomeres, DNA transcription factors and their targeting by bis-intercalating drugs, and DNA topoisomerase I and their targeting by camptothecin anticancer drugs.
Biologically relevant DNA G-quadruplex secondary structures as potential drug targets.
DNA G-quadruplexes are novel DNA secondary structures formed in specific G-rich sequences and have been demonstrated as potential regulatory elements in regions of biological significance. Thus DNA G-quadruplex emerges as a promising new molecular target for anticancer drug design. Indeed, a G-quadruplex-targeting small molecule drug is in phase II clinical trials. We work on the structural analyses of the biologically relevant DNA G-quadruplexes and their interactions with G-quadruplex interacting compounds. Delineating the molecular level details of the biologically relevant G-quadruplexes is important for the evaluation of their potential as cancer therapeutic targets as well as the structure-based rational drug design. Our primary method, high field NMR, represents a major method for structural study of biologically relevant DNA secondary structures, due to the difficulty of crystallization of such structures. Specifically, we work on: 1) DNA G-quadruplexes formed in the oncogene promoter regions, and 2) DNA G-quadruplexes formed in the human telomere.
Targeting DNA and topoisomerase I by camptothecin anticancer drugs.
The camptothecin agents are active against a broad spectrum of cancers and are renowned for their unique mechanism of action–inhibition of human topoisomerase I. Two camptothecins have recently been introduced into cancer clinics, with CPT-11 (Camptosar, Irinotecan) being used for colon cancer and topotecan (Hycamtin, TPT) being used for ovarian and lung cancers. Ongoing clinical trials indicate that camptothecin derivatives will be useful in a variety of other human cancers. However, for all their promise, current clinical camptothecin drugs have two main problems, namely, the instability of the active lactone form and the reversibility of the ternary complex of DNA, Topo I and drug. These two main problems result in the limited in vivo efficacy of CPTs, which is considerably reduced from the in vitro activity. We plan to address these two main problems by determining the important functional groups promoting a more stable lactone and a more stable ternary complex. We will also work to elucidate the structural basis for the specific interactions of these functional groups with target DNA and topoisomerase I.
Targeting DNA binding of transcription factors by novel DNA bisintercalators.
The anticancer drug XR5944, a small molecule bis-phenazine initially developed by the Xenova LTD (UK), shows exceptional anticancer activity both in vitro and in vivo. Originally developed as a dual inhibitor of topoisomerases I/II, the primary mechanism of XR5944 action has recently been shown to be related with transcription inhibition. Recent study from our lab has shown that XR5944 exhibits a novel-binding mode to the DNA major groove. Furthermore, XR5944 is shown to be a potent inhibitor of several DNA transcription factors by inhibiting their DNA binding, such as estrogen receptor (ER) and AP1 proteins. We are working on the determination of the precise mechanisms by which XR5944 and its derivatives inhibit estrogen signaling in human breast cancer cells. Inhibition of ER-signaling through interference with ER-ERE binding at the DNA level represents a novel approach to overcome limitations associated with current estrogen-dependent therapeutic modalities. This information will provide a basic framework for the rational use of XR56944 or its derivatives in the clinical setting. This research may also provide a basis for the development of other transcription factor inhibitors.
BS, University of Science and Technology of China, Hefei, People's Republic of China, 1989, Molecular and Cell Biology
PhD, University of Illinois at Urbana-Champaign, 1996, Biophysics
PD, University of Kentucky, 1996-1998, Pharmaceutical Sciences
Selected Publications:
Punchihewa, C., and Yang, D. “Therapeutic Targets and Drugs-G-quadruplex inhibitors” Telomeres and Telomerase in Cancer, 2009. Keiko Hiyama (Ed.), NJ, USA, Springer. 2009.
Dai, J., Carver, M., Yang D. “Polymorphism of human telomeric G-quadruplex structures” Biochimie 90, 1172-1183, 2008.
Bates, P, Mergny. J.L., and Yang, D. “Quartets in G-major. The First International Meeting on Quadruplex DNA” EMBO report, 8, 1003-1010, 2007.
Dai, J., Carver M., Punchihewa, C., Jones, R. A., and Yang, D. “Structure of the hybrid-2 type intramolecular human telomeric G-quadruplex in K+ solution: Insights into structure polymorphism of the human telomeric sequence.” Nucleic Acid Research, Nucleic Acid Research, 35, 4927-4940, 2007. (cover article)
Ambrus, A. and Yang, D. “Diffusion ordered NMR spectroscopy for analysis of DNA secondary structural elements.” Analytical Biochemistry, 367(1), 56-67, 2007.
Punchihewa, C., Dai, J., Carver, M., and Yang, D. “Human Topoisomerase I C-Terminal Domain Fragment Containing the Active Tyrosine Site is a Molten Globule: Implication for the Formation of Competent Productive Complex.” J. Structural Biology, 159(1), 111-121, 2007.
Dai, J., Punchihewa, C., Ambrus, A., Chen, D., Jones, R. A., and Yang, D. “Structure of the intramolecular human telomeric G-quadruplex in potassium solution: A novel adenine triple formation.” Nucleic Acid Research 35, 2440 - 2450, 2007. (featured on the cover of C&EN, issue of May 28th, 2007.)
Punchihewa, C., De Alba, A., Sidell, N. and Yang, D. “XR5944, a potent inhibitor of estrogen receptors”, Molecular Cancer Therapeutics, 6, 213-219, 2007. (featured in DailyUpdates/LeadDiscovery Headline Articles.)
Dai, J., Chen, D., Jones, R. A., Hurley, L. H., and Yang, D. “NMR solution structure of the major G-quadruplex structure formed in the human BCL2 promoter region.” Nucleic Acid Research, 34, 5133-5144, 2006.
Yang, D. and Hurley, L. H. “Structure of the biologically relevant G-quadruplex in the c-myc promoter.” Nucleosides Nucleotides & Nucleic Acids, 25(8), 951-968,2006.
Hurley, L. H., Siddiqui-Jain, A., and Yang, D. “Drug targeting of the c-myc promoter to repress gene expression via a G-quadruplex silencer element” Seminars in Oncology, 33(4), 498-512, 2006.
Ambrus, A., Chen, D., Dai, J., Bialis, T., Jones, R. A., and Yang, D. “Human telomeric sequence forms a hybrid-type intramolecular G-quadruplex structure with mixed parallel/antiparallel strands in potassium solution.” Nucleic Acid Research 34(9), 2723-2735, 2006 (featured in C&EN, issue of July 31, 2006).
Dai, J., Dexheimer, T. S. Chen, D., Carver, M., Ambrus, A., Jones, R. A., and Yang, D. “An intramolecular G-quadruplex structure with mixed parallel/antiparallel g-strands formed in the human bcl-2 promoter region in solution.” JACS 128(4), 1096 –1098, 2006.
Tangirala, R., Dixon, R., Yang, D., Ambrus, A., Antony, S., Agama, K., Pommier, Y., and Curran D. P., “Total and semisynthesis and in vitro studies of both enantiomers of 20-fluorocamptothecin”, Bioorganic & Medicinal Chemistry Letters 15(21), 4736-4740, 2005.
Ambrus, A., Chen, D., Whatcott, C., Somogyi, Á. and Yang, D. “Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry protocol for monitoring the progress of enzymatic 13C/15N-labeled DNA syntheses”, Analytical Biochemistry, 342(2), 246-253, 2005.
Ambrus, A., Chen, D., Dai, J., Jones, R. A., and Yang, D. “Solution structure of the biologically relevant G-quadruplex element in the human c-MYC promoter. implications for G-quadruplex stabilization.”, Biochemistry 44, 2048-2048, 2005.
Dai, J., Punchihewa, C., Mistry, P., Ooi, A. T., Yang, D. “Novel DNA bis-intercalation by MLN944, a potent clinical bisphenazine anticancer drug”, Journal of Biological Chemistry 279(44): 46096-46103, 2004.
Gu, J., Wang, Y., Franzblau, S.G., Montenegro, G., Yang, D. and Timmermann, B.N. “Antitubercular constituents of Valeriana laxiflora DC.” Planta Medica, 70(6), 509-514, 2004.
Yang, D., Dai. J., and Wang, A. H.-J. “Structures and mechanisms of anticancer drugs-target interactions”, Cancer Chemotherapy and Chemoprevention, Rui Han, Yan Shun, DaoPei Lu (Eds.), Beijing, Science Press. 2003.
Zhang, Y., Yuan, F., Xin, H., Wu, X., Rajpal, D.K., Yang, D. and Wang, Z. “Human DNA polymerase k synthesizes DNA with extraordinarily low fidelity” Nucleic Acids Research, 28(21), 4147-4156, 2000.
Gryczynski, I., Gryczynski, Z., Lakowicz, J.R., Yang, D. and Burke, T.G. "Fluorescence spectral properties of the anticancer drug topotecan by steady-state and frequency-domain fluorometry with one-photon and multi-photon excitation", Photochemistry and Photobiology, 69(4), 421-428, 1999.
Yang, D., Strode, J.T., Spielmann, H.P., Wang, A.H.-J. and Burke, T.G. “DNA interactions of two clinical camptothecin drugs stabilize their active lactone forms” Journal of American Chemical Society 120(12), 2979-2980, 1998 (featured in C&EN, issue of April 7, 1998).
Yang, D. and Wang, A.H.-J. "The structural studies of interactions between anticancer platinum drugs and DNA" (review article) Progress in Biophysics and Molecular Biology 66(1), 81-111, 1996.
vanBoom, S.S.G.E., Yang, D., Reedijk, J., van der Marel, G.A. and Wang, A.H.-J. "Structural effect of intra-strand cisplatin-crosslink on palindromic DNA sequences" Journal of Biomolecular Structure & Dynamics 13(6), 989-998, 1996 (cover article).
Yang, D., van Boom, S.S.G.E., Reedijk, J., van Boom, J.H. and Wang, A.H.-J. "Structure and isomerization of an intra-strand cisplatin-crosslinked octamer DNA duplex by NMR analysis" Biochemistry 34, 12912-12920, 1995.
Yang, D., van Boom, S.S.G.E., Reedijk, J., van Boom, J.H., Farrell, N. and Wang, A.H.-J. "A novel DNA structure induced by the new dinuclear anticancer compound m-(1,4-diaminobutane)-bis[trans-diamminechloroplatinum (II)] crosslinked to a GpC site in DNA" Nature Structural Biology 2(7), 577-586, 1995 (cover article).
Sriram, M., Yang, D., Gao, Y.-G. and Wang, A.H.-J. "Crystal and solution structure of d(CGC[e6G]AATTCGCG)-drug complexes reveal conformational polymorphism of O6-ethyl-Guanine:Cytosine base pair" The New York Academy of Sciences Symposium on DNA damage: Effects on DNA Structure and Protein Recognition. pp18-45, 1994.
Robinson, H., Yang, D. and Wang, A.H.-J. "Structure and dynamics of the antitumor drugs nogalamycin and disnogalamycin complexed to d(CGTACG)2: comparison of crystal and solution structures" Gene 149, 179-188, 1994.
Yang, D. and Wang, A.H.-J. "Structure by NMR of antitumor drugs aclacinomycin A and B complexed to d(CGTACG)" Biochemistry 33, 6595-6604, 1994.
Yang, D., Gao, Y.-G., Robinson, H., van der Marel, G.A., van Boom, J.H. and Wang, A.H.-J. "Structural effects of C2-methylhypoxanthine:cytosine base pair in B-DNA: A combined NMR and X-ray diffraction study of d(CGC[m2I]AATTCGCG)" Biochemistry 32, 8672-8681, 1993.