Danzhou Yang

Danzhou Yang, PhD, is a Professor of Medicinal Chemistry in the College of Pharmacy Department of Pharmacology and Toxicology, a Professor of Chemistry, a Comprehensive member of the Arizona Cancer Center, a Faculty Member of BIO5 Institute, and the Director of the College of Pharmacy NMR facility, at the University of Arizona. Most of the front line anticancer agents are known to interact with DNA or DNA interacting proteins in order to exert their anticancer effects; cancer-specific molecular targets have become a frontier of new anticancer drug development. Dr. Yang’s research is focused on structural and mechanistic studies of DNA-related cancer-specific molecular targets, and structure-based rational drug design of cancer therapeutic intervention. Her laboratory is working on a number of molecular targets for cancer therapeutics, including DNA G-quadruplexes and their drug interactions, DNA bis-intercalating compounds that inhibit transcription factors, and DNA topoisomerase I as an anticancer drug target. Specifically, DNA G-quadruplexes, novel DNA secondary structures formed in regions of biological significance including human telomeres and oncogene promoters, are emerging as a new class of promising cancer-specific molecular targets for small molecule drugs. Her research program involves the implementation of a variety of biophysical and biochemical methods, particularly high-field NMR spectroscopy. NMR represents a major method for structural study of biologically relevant DNA secondary structures.Dr. Yang has been invited to many national and international meetings, including chairing the session “Chemistry in Support of Cancer Drug Discovery” in Chemistry in Cancer Research/AACR-American Chemical Society joint conference in 2009, chairing the Symposium for “G-Quadruplexes as Targets for Drug Discovery and Development” in ACS National meeting in 2010, co-organizing and chairing the 2012 National Medicinal Chemistry Symposium. She is the Co-Chair of the Young Chemist Committee in CICR (Chemistry in Cancer Research) of AACR (American Association for Cancer Research). Dr. Yang’s research has been actively supported by NIH (National Institute of Health), and she is serving on the NIH study sections.
			
Sequence, Stability, And Structure Of G Quadruplexes And Their Interactions With Drugs. Source: Current Protocols In Nucleic Acid Chemistry / Edited By Serge L. Beaucage ... [Et Al.]
September 7th, 2012 PMID: 22956454 Danzhou Yang
Although DNA is most widely known for its ability to store and pass along genetic information, the discovery of G-quadruplex structures has illuminated a new role for DNA in biology. DNA G-quadruplexes are four-stranded globular nucleic acid secondary structures formed in specific G-rich sequences with biological significance, such as human telomeres and oncogene promoters. This review focuses on the unimolecular DNA G-quadruplexes, which can readily form in solution under physiological conditions and are considered to be the most biologically relevant. Available structural data show a great conformational diversity of unimolecular G-quadruplexes, which are amenable to small-molecule drug targeting. The relationships between sequence, structure, and stability of unimolecular DNA G-quadruplexes, as well as the recent progress on interactions with small-molecule compounds and insights into rational design of G-quadruplex-interactive molecules, will be discussed.<br /><br />
The Major G Quadruplex Formed In The Human Platelet Derived Growth Factor Receptor β Promoter Adopts A Novel Broken Strand Structure In K+ Solution. Source: Journal Of The American Chemical Society
August 6th, 2012 PMID: 22866911 Danzhou Yang
Overexpression of platelet-derived growth factor receptor β (PDGFR-β) has been associated with cancers and vascular and fibrotic disorders. PDGFR-β has become an attractive target for the treatment of cancers and fibrotic disorders. DNA G-quadruplexes formed in the GC-rich nuclease hypersensitivity element of the human PDGFR-β gene promoter have been found to inhibit PDGFR-β transcriptional activity. Here we determined the major G-quadruplex formed in the PDGFR-β promoter. Instead of using four continuous runs with three or more guanines, this G-quadruplex adopts a novel folding with a broken G-strand to form a primarily parallel-stranded intramolecular structure with three 1 nucleotide (nt) double-chain-reversal loops and one additional lateral loop. The novel folding of the PDGFR-β promoter G-quadruplex emphasizes the robustness of parallel-stranded structural motifs with a 1 nt loop. Considering recent progress on G-quadruplexes formed in gene-promoter sequences, we suggest the 1 nt looped G(i)NG(j) motif may have been evolutionarily selected to serve as a stable foundation upon which the promoter G-quadruplexes can build. The novel folding of the PDGFR-β promoter G-quadruplex may be attractive for small-molecule drugs that specifically target this secondary structure and modulate PDGFR-β gene expression.<br /><br />
Gaining Insights Into The Small Molecule Targeting Of The G Quadruplex In The C Myc Promoter Using Nmr And An Allele Specific Transcriptional Assay. Source: Topics In Current Chemistry
July 3rd, 2012 PMID: 22752577 Danzhou Yang
G-quadruplexes (four-stranded DNA secondary structures) are showing promise as new targets for anticancer therapies. Specifically, G-quadruplexes in the proximal promoter region of regulatory genes have the potential to act as silencer elements and thereby turn off transcription. Thus, compounds that are capable of binding to and stabilizing G-quadruplexes would be of great benefit. In this chapter we describe two recent studies from our labs. In the first case, we use NMR to elucidate the structure of a 2:1 complex between a small molecule and the G-quadruplex in the c-MYC promoter. In the second case, we use an allele-specific transcription assay to demonstrate that the effect of a G-quadruplex-interactive compound is mediated directly through the G-quadruplex. Finally, we use this information to propose models for the interaction of various small molecules with the c-MYC G-quadruplex.<br /><br />
Solution Structure Of A 2:1 Quindoline C Myc G Quadruplex: Insights Into G Quadruplex Interactive Small Molecule Drug Design. Source: Journal Of The American Chemical Society
October 14th, 2011 PMID: 21967482 Danzhou Yang
Unimolecular parallel-stranded G-quadruplex structures are found to be prevalent in gene promoters. The nuclease hypersensitivity element III(1) (NHE III(1)) of the c-MYC promoter can form transcriptionally active and silenced forms, and the formation of DNA G-quadruplex structures has been shown to be critical for c-MYC transcriptional silencing. The solution structure of a 2:1 quindoline-G-quadruplex complex has been solved and shows unexpected features, including the drug-induced reorientation of the flanking sequences to form a new binding pocket. While both 3' and 5' complexes show overall similar features, there are identifiable differences that emphasize the importance of both stacking and electronic interactions. For the first time, we describe the importance of the shape of the ligand as well as the two flanking bases in determining drug binding specificity. These structures provide important insights for the structure-based rational design of drugs that bind to unimolecular parallel G-quadruplexes commonly found in promoter elements.<br /><br />
C Myc Promoter G Quadruplex Formed At The 5' End Of Nhe Iii1 Element: Insights Into Biological Relevance And Parallel Stranded G Quadruplex Stability. Source: Nucleic Acids Research
July 27th, 2011 PMID: 21795379 Danzhou Yang
We studied the structures and stabilities of G-quadruplexes formed in Myc1234, the region containing the four consecutive 5' runs of guanines of c-MYC promoter NHE III(1,) which have recently been shown to form in a supercoiled plasmid system in aqueous solution. We determined the NMR solution structure of the 1:2:1 parallel-stranded loop isomer, one of the two major loop isomers formed in Myc1234 in K(+) solution. This major loop isomer, although sharing the same folding structure, appears to be markedly less stable than the major loop isomer formed in the single-stranded c-MYC NHE III(1) oligonucleotide, the Myc2345 G-quadruplex. Our NMR structures indicated that the different thermostabilities of the two 1:2:1 parallel c-MYC G-quadruplexes are likely caused by the different base conformations of the single nucleotide loops. The observation of the formation of the Myc1234 G-quadruplex in the supercoiled plasmid thus points to the potential role of supercoiling in the G-quadruplex formation in promoter sequences. We also performed a systematic thermodynamic analysis of modified c-MYC NHE III(1) sequences, which provided quantitative measure of the contributions of various loop sequences to the thermostabilities of parallel-stranded G-quadruplexes. This information is important for understanding the equilibrium of promoter G-quadruplex loop isomers and for their drug targeting.<br /><br />
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