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• B.A. 1994, Chemistry and Environmental Studies, Sonoma State University
• Ph.D. 1999, Organic Chemistry, University of Utah (C. Dale Poulter)
• 1999-2002, NIH Postdoctoral Fellow, The Scripps Research Institute (Dale L. Boger)
• 2002 - 2007 Assistant Professor of Medicinal Chemistry
• 2007 - Present, Associate Professor of Medicinal Chemistry
• 2005 The University of Kansas Center for Teaching Excellence Award
• 2006 American Cancer Society Research Scholar
• 2004 - Present, Full Member, Kansas Cancer Center
• 2006 - Present, Faculty of 1000, Biology
• 2007 - present, Editorial Board, Perspectives in Medicinal Chemistry
• 2008 - present, Editorial Board, Future Medicinal Chemistry
• 2009 American Chemical Society David W. Robertson Award in Medicinal Chemistry
Research in the Blagg Group
The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that are required for the refolding of denatured proteins and the maturation of nascent polypeptides into their biologically active, three-dimensional structures. In fact, numerous proteins represented in all six hallmarks of cancer are dependent upon Hsp90 for conformational maturation. Hsp90 inhibition provides a combinatorial attack on multiple pathways responsible for malignant cell growth and proliferation. Consequently, Hsp90 has emerged as a promising target for the development of cancer chemotherapeutics.
Hsp90 contains two ATP binding sites, and in order to fold nascent polypeptides into biologically active proteins, Hsp90 catalyzes the hydrolysis of ATP. ATP hydrolysis provides the Hsp90 protein folding machinery the requisite energy for folding “client” proteins into their correct three-dimensional conformation. Disruption of this folding process results in the destabilization of Hsp90 “client” protein complexes, which leads to ubiquitination and proteasome-mediated degradation of the protein substrate.
The N-terminal ATP binding site is inhibited by the natural products, geldanamycin (GDA) and radicicol (RDC). Three derivatives of GDA are currently in clinical trials for the treatment of several cancers, whereas, RDC has proven to be inactive in vivo. Unfortunately, GDA exhibits poor solubility and the presence of the quinone moiety leads to cytotoxicity unrelated to Hsp90 inhibition. Therefore, there is tremendous need for the development of new, soluble, and selective inhibitors of the Hsp90 protein folding process. One molecule that we have designed is radamide. Radamide is a chimeric molecule composed of the quinone moiety of GDA and the resorcinol ring of RDC. In vitro, this molecule has proven to be a good inhibitor of Hsp90 and provides a rational starting point for the development of more potent compounds. In addition, we have developed radester and the macrocyclic variant, radanamycin.
The C-terminal ATP binding site was only recently elucidated by one our collaborators, Len Neckers (National Cancer Institute), who demonstrated that the coumarin antibiotics, including novobiocin inhibit the C-terminal ATP binding site and leads to the degradation of Hsp90 client proteins similar to that of N-terminal inhibitors. Unfortunately, novobiocin’s activity is not sufficient for further clinical evaluation and thus provides an additional opportunity for the development of more effective Hsp90 inhibitors. We have developed the most potent C-terminal inhibitors of Hsp90 yet discovered (A4 and DHN2) and have been able to demonstrate that Hsp90 inhibitors possess potent neuroprotective properties for potential use against Alzheimer’s, Parkinson’s, and Multiple Sclerosis.
The major goals for members of the Blagg Research Team are to design, synthesize, and evaluate novel inhibitors of the Hsp90 protein folding process. To achieve these goals, we use computer modeling to design new molecules to bind to these ATP binding sites, we develop new organic reactions that allow access the desired compounds in a highly efficient manner, and finally we develop assays that are suitable for determining the biological effects of our rationally designed Hsp90 inhibitors. In addition, we are currently engaged in more than 30 collaborative studies with researchers throughout the world!
For More Information, Please Contact:
Dr. Brian S. J. Blagg
Department of Medicinal Chemistry
4070 Malott Hall
Tel: 785-864-4495
FAX: 785-864-5326
email: bblagg@ku.edu
