Education

1983 – B.A., Wesleyan University, Middletown, CT (Chemistry)
1991 – PhD., Columbia University, New York, NY (Chemistry)
1994 – Post-doctoral Fellow, Harvard University, Cambridge, MA

Honors & Awards

1982 - 1983 – Silverman Award, Wesleyan University
1991 - 1994 – National Institute of Health Post-Doctoral fellowship, Harvard University
1994 - 1995 – Glaxo Fellow, Harvard University
1994 - 1996 – Faculty Fellow, Harvard University

Special National Responsibilities

1998, 1999, 2001 – National Institute of Health, Experimental Therapeutics, Study Section, ad hoc member
2003-2005, 2009, 2016 – National Institute of Health, Drug Discovery and Molecular Therapeutics (DMP), ad hoc
2000-2004 – National Institute of Health, Special Emphasis Panels, Member
2005 – National Institute of Health, Developmental Therapeutics Program Review Panel
2005 – Leukemia & Lymphoma Society, ad hoc reviewer
2010-2013 – National Institute of Health, Drug Discovery and Molecular Therapeutics (DMP), charter member
2012-2013, 2017 – National Institute of Health, Drug Discovery and Molecular Therapeutics (DMP), vice-chair
2012 – National Institute of Health, National Cancer Institution Provocative Questions Review Panel
2014 - 2017 – AIRC (Italy)

Special Local Responsibilities

2004 – University of Washington, Molecular and Cellular Biology Program, admissions committee
2010 – Human Biology faculty search committee
2010, 2017 – Weintraub Award selection committee
2012, 2017 – MCB Program admissions committee
2012 - present – Health Disparities Research Center Internal Advisory Group
2013 - present – Proteomics Scientific Advisory Committee (FHCRC)
2013 - present – Scientific Communications Advisory Committee
2013 - present – Summer Undergraduate Research Program, Co-Director
2014 - present – “Science Spotlight” faculty mentor

Expertise and Research Interests

The overarching goal of research in the Simon laboratory is the development of small molecules as mechanistic probes for a variety of cellular processes and as potential lead compounds for the development of therapeutic agents.  To this end we apply an interdisciplinary approach ranging from chemical synthesis and medicinal chemistry to genetics and cell biology.  The compounds we are studying have been identified from large collections of synthetic, drug-like compounds and from natural sources.  A majority of screens are phenotypic and unbiased in terms of specific targets.  While screening compound libraries is a significant part of what we do the majority of our efforts go into target identification, mechanistic studies to understand the biology and pharmacology of lead compounds and efforts to improve their activity through chemical synthesis of analogs.

The clinical use of several effective drugs is limited because of drug-induced hearing loss.  Aminoglycoside antibiotics (e.g. gentamicin), platinum-based cancer drugs (e.g. cisplatin) and loop diuretics (e.g. furosemide) can cause significant and in many cases irreversible hearing loss due to selective toxicity to auditory hair cells.  The mechanism of hair cell death, also called ototoxicity, is poorly understood.  In collaboration with Ed Rubel’s laboratory at the Bloedel Center for Hearing Research, Department of Otolaryngology and Dave Raible’s laboratory in the Department of Biological Structure both at the University of Washington, we carried out a 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.  Dr. Rubel’s laboratory showed that our lead compound, PROTO1, also protects rat auditory hair cells and preserves hearing following doses of kanamycin that induce significant hearing loss in control animals.  We are currently working to optimize PROTO compounds for in vivo use and also to identify their molecular target.  Protection from hearing loss caused by drugs may also lead to the development of drugs for noise- and age-related hearing loss.

We identified inhibitors of yeast (S. cerevisiae) and human NAD-dependent deacetylases using yeast cell-based phenotypic screens.  In humans, there are seven NAD-dependent deacetylases called the sirtuins.  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 (FHCRC), we are working to optimize our sirtuin-1 and 2 inhibitors using medicinal chemistry strategies for use as anti-lymphoma therapeutics.