Dr. Chang obtained B.S. degrees in biological sciences and chemistry from the University of Southern California, and a Ph.D. in chemistry from the University of Chicago. Subsequently, she conducted postdoctoral research at Columbia University as a National Institutes of Health postdoctoral fellow. She joined the faculty of the University of Notre Dame in 2003. Previously, Dr. Chang was Chief Operating Officer of University Research Network, Inc., Senior Scientist with Pharmacia Corporation, and Senior Chemist at Dow Chemical Company. She has characterized the ADME properties of numerous drugs, as well as prepared NDAs, INDs, Investigator's Brochures, product development plans, and candidate drug evaluations.
The Chang lab conducts biomedical research to understand the molecular basis of disease and to design small molecules for therapeutic intervention. Some of our current projects are:
SB-3CT is a selective gelatinase (MMP-2 and MMP-9) inhibitor that shows efficacy in animal models of stroke, traumatic brain injury, and cancer metastasis. SB-3CT, however, is poorly water soluble and is extensively metabolized. We used a prodrug strategy to increase >5000-fold the aqueous solubility of SB-3CT. The prodrugs are hydrolyzed in human blood within 30 minutes, generating the active gelatinase inhibitors. One of the prodrugs (referred to as ND-478) has excellent pharmacokinetic properties. This class of compounds is rapidly absorbed andis readily distributed to the brain. Efficacy studies in animal models of stroke and traumatic brain injury are currently being conducted.
Chronic wounds are a complication of diabetes and are characterized by inflammation, altered MMP expression, and deregulation of apoptosis. We used an affinity resin that binds only the active forms of MMPs and related ADAMs coupled with quantitative proteomics to identify active MMPs in diabetic wounds. Using the selective MMP-9 inhibitor ND-322 led to acceleration of wound healing accompanied by re-epithelialization. This represents the first pharmacological intervention in treatment of diabetic wounds. Studies to confirm the roles of these MMPs in diabetic wound healing are underway.
Another project involves the design, syntheses, and evaluation of novel antibiotics to treat methicillin-resistant Staphylococcus aureus infections. We have identified two lead templates that show high in vitro activity and promising antibacterial activity in a mouse model of infection. Their pharmacokinetic properties are being optimized. Identification of the target is being pursued by photoaffinity labeling at the whole proteome level, as well as obtaining an X-ray crystal structure of the compounds with the putative target.
Zhang, H.; Chang, M.; Hansen, C. N.; Basso, M.; Noble-Haeusslein, L. J. Role of Matrix Metalloproteinases and Therapeutic Benefits of Their Inhibition in Spinal Cord Injury. Neurotherapeutics 2011, 8, 206-220.
Gooyit, M.; Lee, M.; Schroeder, V. A.; Ikejiri, M.; Suckow, M. A.; Mobashery, S.; Chang, M. Selective Water-soluble Gelatinase Inhibitor Prodrugs. J. Med. Chem. 2011, 54, 6676-6690. Link
Gooyit, M.; Suckow, M. A.; Schroeder, V. A.; Wolter, W. R.; Mobashery, S.; Chang, M. Selective Gelatinase Inhibitor Neuroprotective Agents Cross the Blood-brain Barrier. ACS Chem. Neurosci. 2012, doi:10.1021/cn3000062w, e-published ahead of print, in press.
Gooyit, M.; Lee, M.; Hesek, D.; Boggess, B.; Oliver, A. G.; Fridman, R.; Mobashery, S.; Chang, M. Synthesis, Kinetic Characterization and Metabolism of Diastereomeric 2-(1-(4-Phenoxyphenylsulfonyl)ethyl)thiiranes as Potent Gelatinase and MT1-MMP Inhibitors. Chem. Biol. Drug Design, 2009, 74, 535-546. Link