Department of Chemistry & Biochemistry

Biography

2017-Present

Director, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame

2017-Present

Charles Huisking Professor of Chemistry and Biochemistry, University of Notre Dame

2014-2017

Lester and Betty Mitscher Professor, University of Kansas

2010-2017

Professor of Medicinal Chemistry, University of Kansas

2007-2010

Associate Professor of Medicinal Chemistry, University of Kansas

2002-2007

Assistant Professor of Medicinal Chemistry, University of Kansas

1999-2002

NIH Postdoctoral Fellow, The Scripps Research Institute

1999

Ph.D. in Organic Chemistry, University of Utah

1994

B.A. in Chemistry and Environmental Studies, Sonoma State University

Co-founder, Grannus Therapeutics

Editorships

2018-Present

Editorial Board, International Journal of Molecular Sciences

2011-2021

Associate Editor, The Journal of Medicinal Chemistry

2010-Present

Editorial Consulting Board, Bioorganic and Medicinal Chemistry

2010-Present

Editorial Consulting Board, Bioorganic and Medicinal Chemistry Letters

2009-Present

Editorial Advisory Board, ACS Medicinal Chemistry Letters

2008-Present

Editorial Board, Future Medicinal Chemistry

2007-Present

Editorial Board, Perspectives in Medicinal Chemistry

Selected Awards

2015

Baxendale Innovation Award, University of Kansas

2013

Leading Light Award, University of Kansas

2012

Kentucky Colonel

2011

University of Kansas Scholarly Achievement Award

2009

American Chemical Society David W. Robertson Award in Medicinal Chemistry

2006

American Cancer Society Research Scholar Award

2006

Faculty of 1000, Biology

2005

University of Kansas Outstanding Teacher

Research Interests

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!

Recent Publications

• Spielbauer, K. K.; Subramanian, C.; Cousineau, E.; Abdallah, L.; Jurecki, L.; Blagg, B. and Cohen, M. "C-Terminal hsp90 Inhibitors Overcome MEK and BRAF Inhibitor Resistance in Melanoma Dysplasia" 2022 Annals of Surgical Oncology, 29, pp.353.
• Pipalia, N. H.; Saad, S. Z.; Subramanian, K.; Cross, A.; Al-Motawa, A.; Garg, K.; Blagg, B.; Neckers, L.; Helquist, P.; Wiest, O.; Ory, D. S. and Maxfield, F. R. "HSP90 Inhibitors Reduce Cholesterol Storage in Niemann-Pick Type C1 Mutant Fibroblasts" 2021 Journal of Lipid Research, 62, 10114. DOI: 10.1016/j.jlr.2021.100114.
• Chaudhury, S.; Meka, P. N.; Banerjee, M.; Kent, C. N. and Blagg, B. "Structure-Based Design, Synthesis, and Biological Evaluation of Hsp90 Beta-Selective Inhibitors" 2021 Chemistry-A European Journal, 27 (59), pp.14747-14764. DOI: 10.1002/chem.202102574.
• Kurop, M. K.; Huyen, C. M.; Kelly, J. H. and Blagg, B. "The Heat Shock Response and Small Molecule Regulators" 2021 European Journal of Medicinal Chemistry, 226, 113846. DOI: 10.1016/j.ejmech.2021.113846.
• Rodriguez, Y. A.; Kaur, S.; Nolte, E.; Zheng, Z.; Blagg, B. and Dobrowsky, R. T. "Novologue Therapy Requires Heat Shock Protein 70 and Thioredoxin-Interacting Protein to Improve Mitochondrial Bioenergetics and Decrease Mitophagy in Diabetic Sensory Neurons" 2021 ACS Chemical Neuroscience, 12 (16), pp.3049-3059. DOI: 10.1021/acschemneuro.1c00340.
• Zhou, J.; Gelot, C.; Pantelidou, C.; Li, A.; Yucel, H.; Davis, R. E.; Farkkila, A.; Kochupurakkal, B.; Syed, A.; Shapiro, G. I.; Tainer, J. A.; Blagg, B.; Ceccaldi, R. and D'Andrea, A. D. "A First-in-Class Polymerase Theta Inhibitor Selectively Targets Homologous-Recombination-Deficient Tumors" 2021 Nature Cancer, 2 (6), pp.598-+. DOI: 10.1038/s43018-021-00203-x.

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