- Director, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame
- Charles Huisking Professor of Chemistry and Biochemistry, University of Notre Dame
- Lester and Betty Mitscher Professor, University of Kansas
- Professor of Medicinal Chemistry, University of Kansas
- Associate Professor of Medicinal Chemistry, University of Kansas
- Assistant Professor of Medicinal Chemistry, University of Kansas
- NIH Postdoctoral Fellow, The Scripps Research Institute
- Ph.D. in Organic Chemistry, University of Utah
- B.A. in Chemistry and Environmental Studies, Sonoma State University
- Baxendale Innovation Award, University of Kansas
- Leading Light Award, University of Kansas
- Kentucky Colonel
- University of Kansas Scholarly Achievement Award
- American Chemical Society David W. Robertson Award in Medicinal Chemistry
- American Cancer Society Research Scholar Award
- Faculty of 1000, Biology
- University of Kansas Outstanding Teacher
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 ten 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 ubiquitinylation 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). Numerous (~20) analogs of these natural products as well as the nucleotide itself have undergone clinical evaluation for the potential treatment of cancer. Unfortunately, the vast majority of these molecules have failed. The current hypothesis is that on-target toxicities are produced when all four Hsp90 isoforms are targeted simultaneously. Therefore, we are working towards the development of the first isoform selective Hsp90 inhibitors and have produced the first Grp94-selective inhibitor and most recently, the first Hsp90β-selective inhibitor. Both of these manifest biological activities that are likely to be useful for the treatment of disease.
The C-terminal ATP binding site was identified by one of our collaborators, Len Neckers (National Cancer Institute), who demonstrated that the coumarin antibiotics, including novobiocin, inhibit the C-terminal ATP binding site and lead to the degradation of Hsp90 client proteins similarly to N-terminal inhibitors. Unfortunately, novobiocin's activity is not sufficient for further clinical evaluation and thus represents an opportunity to develop more efficacious Hsp90 inhibitors. We have developed the most potent C-terminal inhibitors of Hsp90 yet discovered and have demonstrated the Hsp90 inhibitors possess potent neuroprotective activities against Alzheimer's, Parkinson's, diabetic peripheral neuropathy, and Multiple Sclerosis. Through optimization of the scaffold, we have produced a neuroprotective agent that is currently in Phase I human clinical trials for neuropathy.
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 that bind these ATP-binding sites, we develop new organic reactions that allow access to 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. We are currently engaged in more than 50 collaborative studies with researchers throughout the world!
- Khandelwal, A., Kent, C.N., Balch, M., Peng, S., Mishra, S.J., Deng, J., Day, V.W., Liu, W., Subramanian, C., Cohen, M., Holzbeierlein, J.M., Matts, R., Blagg, B.S.J. "Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitor" 2018 Nature Communications, 9 (1), 425. DOI: 10.1038/s41467-017-02013-1
- Zhang, Z., You, Z., Dobrowsky, R.T., Blagg, B.S.J. "Synthesis and evaluation of a ring-constrained Hsp90 C-terminal inhibitor that exhibits neuroprotective activity" 2018 Bioorganic and Medicinal Chemistry Letters, 28 (16), pp. 2701-2704. DOI: 10.1016/j.bmcl.2018.03.071
- Forsberg, L.K., Davis, R.E., Wimalasena, V.K., Blagg, B.S.J. "Exploiting polarity and chirality to probe the Hsp90 C-terminus" 2018 Bioorganic and Medicinal Chemistry, 26 (12), pp. 3096-3110. DOI: 10.1016/j.bmc.2018.04.028
- Huard, D.J.E., Crowley, V.M., Du, Y., Cordova, R.A., Sun, Z., Tomlin, M.O., Dickey, C.A., Koren, J., III, Blair, L., Fu, H., Blagg, B.S.J., Lieberman, R.L. "Trifunctional High-Throughput Screen Identifies Promising Scaffold to Inhibit Grp94 and Treat Myocilin-Associated Glaucoma" 2018 ACS Chemical Biology, 13 (4), pp. 933-941. DOI: 10.1021/acschembio.7b01083
- Que, N.L.S., Crowley, V.M., Duerfeldt, A.S., Zhao, J., Kent, C.N., Blagg, B.S.J., Gewirth, D.T. "Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 to Optimize Paralog-Selective Binding" 2018 Journal of Medicinal Chemistry, 61 (7), pp. 2793-2805. DOI: 10.1021/acs.jmedchem.7b01608
- Byrd, K.M., Blagg, B.S.J. "Chaperone substrate provides missing link for cancer drug discovery" 2018 Journal of Biological Chemistry, 293 (7), pp. 2381-2382. DOI: 10.1074/jbc.H118.001591
- Charles Huisking Professor; Director, Warren Family Research Center for Drug Discovery and Development
- Office: 305G McCourtney Hall
- Phone: 574-631-6877
- Send an email
- Visit Website