The clinical use of several effective drugs is limited because of debilitating side effects. Aminoglycoside antibiotics (e.g. amikacin), platinum-based cancer drugs (e.g. cisplatin) and loop diuretics (e.g. furosemide) can cause significant and in many cases irreversible hearing loss and life-threatening kidney damage. Hearing loss due to mechanosensory hair cell death, also called ototoxicity, is poorly understood. Likewise, the damage to proximal tubule cells in the kidney remains largely undetermined. In collaboration with Ed Rubel’s laboratory at the Bloedel Center for Hearing Research and Dave Raible’s laboratory in the Department of Biological Structure both at the University of Washington, we carried out a small molecule drug screen using zebrafish mechanosensory hair cells as a model system for mammalian auditory hair cells. This screen identified a family of small molecule inhibitors of aminoglycoside-induced hair cell death in zebrafish and mammals. Significantly, the most potent of these compounds also protect against cisplatin-induced hair cell death in zebrafish. Through medicinal chemistry optimization, we developed ORC-13661, a pre-clinical candidate with suitable pharmacokinetic and toxicological properties for use in human patients. We are currently working with staff at the National Institute of Allergy and Infectious Diseases and National Institute on Deafness and Other Communication Disorders to design safety and efficacy studies in humans. We are also actively working on determining the mechanism of action and molecular target of the protective compounds.
Owens, K.N., Santos, F., Roberts, B., Linbo, T., Coffin, A.B., Knisley, A.J., Simon, J.A., Rubel, E.W., and Raible, D.W. "Identification of Genetic and Chemical Modulators of Zebrafish Mechanosensory Hair Cell Death" PLoS Genet. 4(2): e1000020. doi:10.1371/journal.pgen.1000020 (2008)
Thomas A.J., Wu P., Raible D.W., Rubel E.W., Simon J.A., Ou H.C., “Identification of small molecule inhibitors of cisplatin-induced hair cell death: results of a 10,000 compound screen in the zebrafish lateral line.”, Otol. Neurotol., 36(3), 519-25 (2015)
We identified inhibitors of yeast (S. cerevisiae) and human NAD+-dependent deacetylases using cell-based phenotypic screens from a library of diverse, drug-like compounds. In humans, there are seven NAD+-dependent deacetylases called the sirtuins (SIRT1-7). These ubiquitous enzymes have been shown to play roles in functions ranging from transcriptional modulation to DNA damage responses and modulators of specific sirtuins have been suggested as therapeutic agents for a variety of human diseases. In collaboration with Toni Bedalov’s laboratory at Fred Hutch, we are working to optimize our sirtuin-2 inhibitors using medicinal chemistry strategies for use as anti-lymphoma therapeutics.
Heltweg, B., Gatbonton, T., Schuler, A. D., Posakony, J., Li, H., Goehle, S., Kollipara, R., DePinho, R. A., Gu, Y., Simon, J. A., Bedalov A., "Antitumor activity of a small molecule inhibitor of human Silent Information Regulator 2 enzymes" Cancer Res., 66, 4368-77 (2006).
Mahajan, S.S., Scian, M., Sripathy, S., Posakony, J., Lao, U., Loe, T.K., Leko, V., Thalhofer, A., Schuler, A.D., Bedalov, A., Simon, J.A., “Development of Pyrazolone and Isoxazol-5-one Cambinol Analogs as Sirtuin Inhibitors” J.Med. Chem., 57(8), 3283-94 (2014)