Ph.D., Columbia University, Chemistry, 1991.
The overall aim of the research carried out in our lab is to identify new anticancer drugs. To accomplish this aim, we use a wide range of experimental techniques ranging from organic synthesis to genetic screens in model organisms and drug screens in human cell lines. We also use a number of experimental systems ranging from budding yeast to mammalian cell lines. A large part of our research involves drug screens. We have pursued two strategies for identifying new anticancer drugs. First, we have carried out screens in which we use the genetic context of the cancer cell as the drug target. We identify compounds that are selectively toxic to cells that contain the "cancer context" but are non-toxic to normal cells. This type of phenotypic approach does not depend on a precise knowledge and understanding of the biology of cancer cells, in fact, it does not require choosing a specific protein target and consequently, does not risk choosing the wrong target. An additional aspect of this approach is that we need to identify the molecular targets of our lead compounds. For this reason, we are also developing high throughput, genome-wide strategies for drug target identification. We have focused on compounds that target cells with defects in chromosome segregation and the checkpoint that normally protects cells from chromosome mis-segregation.
The second broad strategy is to use chemical genetics to find more specific anticancer drugs. Chemical genetics is a combination of traditional phenotype-based screens with modern tools for discovery of therapeutic agents. We have focused on eukaryotic NAD-dependent deacetylases, an enzyme class that plays key roles in stress and DNA damage responses as well as life span regulation in organisms ranging from baker's yeast to humans. Using chemical genetics, we have identified a class of NAD-dependent deacetylase, or sirtuin, inhibitors and have used these compounds to discovery new functions of these enzymes as well as validate them as therapeutic targets.
Other projects in the lab include the study of genetic interactions of mismatch repair mutants with ribonucleotide reductase as a potential strategy for the identification of drugs for the treatment of tumors with mismatch repair defects.
Biomolecular Structure and Design Program, University of Washington
Molecular and Cellular Biology Program, University of Washington
1994-1996, Faculty Fellow, Harvard University, Chemistry
Identification of small molecule inhibitors of cisplatin-induced hair cell death: results of a 10,000 compound screen in the zebrafish lateral line.. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 36(3):519-25.. 2015.
Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis.. Oncotarget. 5(5):1352-62.. 2014.
Development of Pyrazolone and Isoxazol-5-one Cambinol Analogues as Sirtuin Inhibitors.. Journal of medicinal chemistry. 57(8):3283-94.. 2014.
Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(10):4405-14.. 2013.
Enterocyte-Specific Inactivation of SIRT1 Reduces Tumor Load in the APC(+/min) Mouse Model.. PloS one. 8(6):e66283.. 2013.
Quinoline Ring Derivatives Protect Against Aminoglycoside-Induced Hair Cell Death in the Zebrafish Lateral Line.. Journal of the Association for Research in Otolaryngology : JARO.. 2012.
Tailored magnetic nanoparticles for optimizing magnetic fluid hyperthermia.. Journal of biomedical materials research. Part A. 100(3):728-37.. 2012.
Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin.. Molecular cancer. 11(1):26.. 2012.
Hair Cell Toxicity in Anti-cancer Drugs: Evaluating an Anti-cancer Drug Library for Independent and Synergistic Toxic Effects on Hair Cells Using the Zebrafish Lateral Line.. Journal of the Association for Research in Otolaryngology : JARO. 12(6):719-728.. 2011.
Dinoxin B, a withanolide from Datura inoxia leaves with specific cytotoxic activities.. Journal of natural products. 74(2):267-71.. 2011.
Sirtuin modulators.. Handbook of experimental pharmacology. (206):241-55.. 2011.
Chemical screening for hair cell loss and protection in the zebrafish lateral line.. Zebrafish. 7(1):3-11.. 2010.
A proteomic investigation of ligand-dependent HSP90 complexes reveals CHORDC1 as a novel ADP-dependent HSP90-interacting protein.. Molecular & cellular proteomics : MCP. 9(2):255-70.. 2010.
Drug screening for hearing loss: using the zebrafish lateral line to screen for drugs that prevent and cause hearing loss.. Drug discovery today. 15(7-8):265-71.. 2010.
Identification of FDA-approved drugs and bioactives that protect hair cells in the zebrafish (Danio rerio) lateral line and mouse (Mus musculus) utricle.. Journal of the Association for Research in Otolaryngology : JARO. 10(2):191-203.. 2009.
Identification and characterization of small-molecule inhibitors of hepsin.. Molecular cancer therapeutics. 7(10):3343-51.. 2008.
A small-molecule inhibitor of Tcf/beta-catenin signaling down-regulates PPARgamma and PPARdelta activities.. Molecular cancer therapeutics. 7(3):521-9.. 2008.
Chemotypic variation of essential oils in the medicinal plant, Anemopsis californica.. Phytochemistry. 69(4):919-27.. 2008.
Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death.. PLoS genetics. 4(2):e1000020.. 2008.
Identification of small molecules inducing apoptosis by cell-based assay using fission yeast deletion mutants.. Investigational new drugs. 26(4):299-307.. 2008.