Danzhou Yang, PhD
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
Danzhou Yang and Andrew H.-J. Wang "Structure by NMR of Antitumor Drugs Aclacinomycin A and B Complexed to d(CGTACG)" Biochemistry 33, 6595-6604, 1994.
Danzhou Yang, Stella S. G. E. van Boom, Jan Reedijk, Jacques H. van Boom, Nicholas Farrell and Andrew H.-J. Wang "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 vol 2 No. 7, 577-586, 1995. (cover article)
Danzhou Yang, Stella S. G. E. van Boom, Jan Reedijk, Jacques van Boom and Andrew H.-J. Wang "Structure and Isomerization of an Intra-strand Cisplatin-crosslinked Octamer DNA Duplex by NMR Analysis" Biochemistry 34, 12912-12920, 1995.
Danzhou Yang and Andrew H.-J. Wang "The Structural Studies of Interactions between Anticancer Platinum Drugs and DNA" Progress in Biophysics and Molecular Biology vol. 66 No.1, 81-111, 1996.
Danzhou Yang, J. Thompson Strode, H. Peter Spielmann, Andrew H.-J. Wang and Thomas G. Burke “DNA Interactions of Two Clinical Camptothecin Drugs Stabilize Their Active Lactone Forms” J. of American Chemical Society vol. 120, No. 12, 2979-2980, 1998.
Jixun Dai, Chandanamalie Punchihewa, Prakash Mistry, Aik Teong Ooi,Danzhou Yang “Novel DNA Bis-intercalation by MLN944, a Potent Clinical Bisphenazine Anticancer Drug”, J. Biological Chemistry,279 (44), 46096-46103, 2004.
Attila Ambrus, Ding Chen, Jixun Dai, Roger A. Jones, Danzhou Yang “Solution Structure of the Biologically Relevant G-Quadruplex Element in the Human c-MYC Promoter. Implications for G-Quadruplex Stabilization.” Biochemistry, 44, 2048-2058, 2005.
Attila Ambrus, Ding Chen, Clifford Whatcott, Árpád Somogyi and Danzhou Yang “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.
Laurence H. Hurley, Daniel D. Von Hoff, Adam Siddiqui-Jain, and Danzhou Yang “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.
Danzhou Yangand Laurence Hurley “Structure of The Biologically Relevant G-Quadruplex in the C-MYC Promoter.” Nucleosides Nucleotides & Nucleic Acids, 25(8), 951-968, 2006.
Jixun Dai, Thomas S. Dexheimer, Ding Chen, Megan Carver, Attila Ambrus, Roger A. Jones, Danzhou Yang“An Intramolecular G-Quadruplex Structure with Mixed Parallel/Antiparallel G-strands Formed in the Human BCL-2 Promoter Region in Solution.” J. of American Chemical Society128,1096 –1098, 2006.
Attila Ambrus, Ding Chen, Jixun Dai, Tiffanie Bialis, Roger A. Jones, Danzhou Yang “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.)
Jixun Dai, Ding Chen, Roger A. Jones, Laurence H. Hurley, Danzhou Yang “NMR Solution Structure of the Major G-Quadruplex Structure Formed in the Human BCL-2 Promoter Region.” Nucleic Acid Research34, 5133-5144, 2006.
Chandanamalie Punchihewa, Adrian De Alba, Neil Sidell,Danzhou Yang “XR5944, a potent inhibitor of estrogen receptors”, Molecular Cancer Therapeutics6, 213-219, 2007. (featured in DailyUpdates/LeadDiscovery Headline Articles.)
Jixun Dai, Chandanamalie Punchihewa, Attila Ambrus, Ding Chen, Roger A. Jones, Danzhou Yang “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.)
Chandanamalie Punchihewa, Jixun Dai, Megan Carver,Danzhou Yang “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.
Attila Ambrus and Danzhou Yang“Diffusion ordered NMR spectroscopy for analysis of DNA secondary structural elements.” Analytical Biochemistry,367(1), 56-67,2007.
Jixun Dai, Megan Carver, Chandanamalie Punchihewa,Roger A. Jones, and Danzhou Yang“Structureof the hybrid-2 type intramolecular human telomeric G-quadruplex in K+ solution: Insights into structure polymorphism of the human telomeric sequence.” Nucleic Acid Research,35, 4927-4940, 2007. (cover article)
Paula Bates*, Jean-Louis Mergny*and Danzhou Yang*, (* denotes equal contribution and MS correspondence)“Quartets in G-major. The First International Meeting on Quadruplex DNA” EMBO report, 8, 1003-1010, 2007.
Jixun Dai, Megan Carver, Danzhou Yang“Polymorphism of human telomeric G-quadruplex structures” Biochimie 90, 1172-1183, 2008.
Chandanamalie Punchihewa, Danzhou Yang “Therapeutic Targets and Drugs-G-quadruplex inhibitors” Cancer Drug Discovery and Development: Telomeres and Telomerase in Cancer, Keiko Hiyama (Ed.), Humana Press, Springer (NJ, USA). 251-280, 2009.
Jixun Dai, Attila Ambrus, Laurence H. Hurley, Danzhou Yang. “A direct and nondestructive approach to determine the folding structure of the I-motif DNA secondary structure by NMR.” Communication, J Am Chem Soc 131(17): 6102-4, 2009.
Chandanamalie Punchihewa,Megan Carver, Danzhou Yang. “DNA sequence selectivity of human topoisomerase I-mediated DNA cleavage induced by camptothecin.” Protein Sci. 18(6): 1326-31, 2009.
Zhenjiang Zhang, Jixun Dai, Elizabeth Veliath, Roger A. Jones, and Danzhou Yang. “Structure of a two-G-tetrad intramolecular G-quadruplex formed by a variant human telomeric sequence in K+ solution: insights into the interconversion of human telomeric G-quadruplex structures.”Nucleic Acid Research, 38(3): 1009-21. 2010.
Danzhou Yangand Keika Okamoto “Structural Insights Into G-Quadruplexes: Towards New Anti-Cancer Drugs.” Future Medicinal Chemistry, Vol. 2, No. 4, 619-646, April 2010.
Feng-jue Shu, Neil Sidell, Danzhou Yang, Caleb B. Kallen “The Tri-Nucleotide Spacer Sequence Between Estrogen Response Element Half-Sites is Conserved and Modulates ERα-Mediated Transcriptional Responses.” Journal of Steroid Biochemistry and Molecular Biology, Vol. 120, Issues 4-5, 172-179,June 2010.
Jixun Dai, Emmanuel Hatzakis, Laurence H. Hurley, Danzhou Yang. “I-motif structures formed in the human c-MYC promoter are highly dynamic–Insights into sequence redundancy and I-motif stability” PLoS ONE, 5(7): e11647, Jul 19 2010.
Emmanuel Hatzakis, Keika Okamoto, Danzhou Yang. “Thermodynamic stability and folding kinetics of the major G-quadruplex and its loop isomers formed in the Nuclease Hypersensitive Element in the human c-Myc promoter: Effect of loops and flanking segments on the stability of parallel-stranded intramolecular G-quadruplexes” Biochemistry, 49(43): 9152-60, Nov 2, 2010.
Raveendra I. Mathad and Danzhou Yang“G-Quadruplex Structures and G-Quadruplex-interactive Compounds”Telomeres and Telomerase: Methods Mol Biol, 735:77-96, 2011.
Neil Sidell, Raveendra I. Mathad, Feng-jue Shu, Zhenjiang Zhang, Caleb B. Kallen, Danzhou Yang “Intercalation of XR5944 with the estrogen response element is modulated by the tri-nucleotide spacer sequence between half-sites.” Journal of Steroid Biochemistry and Molecular Biology, 124: 121-127, 2011.
Raveendra I. Mathad, Emmanuel Hatzakis, Jixun Dai, and Danzhou Yang “c-Myc promoter G-quadruplex formed at the 5’-end of NHE III1 element: insights into biological relevance and parallel-stranded G-quadruplex stability” Nucleic Acid Research, 39(20):9023-9033,2011
Jixun Dai, Megan Carver, Laurence H. Hurley, Danzhou Yang “Solution structure of a 2:1 quindoline–c-MYC G-quadruplex. Drug-induced reorientation of the flanking sequence and implications for drug design”, J Am Chem Soc, 133 (44), 17673–17680, 2011
Yuwei Chen, Prashansa Agrawal, Robert V. Brown, Emmanuel Hatzakis, Laurence Hurley, Danzhou Yang “The Major G-Quadruplex Formed in the Human Platelet-Derived Growth Factor Receptor b (PDGFR-b) Promoter Adopts a Novel Broken-Strand Primarily Parallel Structure”, J. Am. Chem. Soc. 134 (32), pp 13220–13223,2012.
Christine Kaiser, Vijay Gokhale, Danzhou Yang, Laurence Hurley “Gaining Insights into the Small Molecule Targeting of the G-Quadruplex in the c-MYC Promoter Using NMR and an Allele-Specific Transcriptional Assay”, Topics in Current Chemistry, 2012 Jul 3.
Yuwei Chen, and Danzhou Yang “Sequence, Stability, Structure of G-Quadruplexes and Their Drug Interactions”, Current Protocols in Nucleic Acid Chemistry, 2012