Brian Blagg

Charles Huisking Professor; Director, Warren Center for Drug Discovery and Development

305G Mccourtney Hall
Notre Dame, IN 46556
+1 574-631-6877


Research Areas

  • Biochemistry
  • Organic Chemistry

Research Specialties

  • Life Processes
  • Medicine
  • Synthesis

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Year Title
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


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!

Selected Publications

  • Dou, X. Z.; Guo, H.; D'Amico, T.; Abdallah, L.; Subramanian, C.; Patel, B. A.; Cohen, M.; Rubinstein, J. L. and Blagg, B. "CryoEM Structure with ATP Synthase Enables Late-Stage Diversification of Cruentaren A" 2023 Chemistry-A European Journal, 29, e202300262. DOI: 10.1002/chem.202300262.
  • Zhu, Y. N.; Zhao, Y.; Wen, J. L.; Liu, S.; Huang, T. H.; Hatial, I.; Peng, X. X.; Al Janabi, H.; Huang, G.; Mittlesteadt, J.; Cheng, M.; Bhardwaj, A.; Ashfeld, B. L.; Kao, K. R.; Maeda, D. Y.; Dai, X.; Wiest, O.; Blagg, B.; Lu, X. M.; Cheng, L.; Wan, J. and Lu, X. "Targeting the Chromatin Effector Pygo2 Promotes Cytotoxic T Cell Responses and Overcomes Immunotherapy Resistance in Prostate Cancer" 2023 Science Immunology, 8 (81), eade4656. DOI: 10.1126/sciimmunol.ade4656.
  • Amatya, E. and Blagg, B. "Recent Advances Toward the Development of Hsp90 C-Terminal Inhibitors" 2023 Bioorganic & Medicinal Chemistry Letters, 80, 129111. DOI: 10.1016/j.bmcl.2022.129111.
  • Keegan, B. M. and Blagg, B. "A Split Renilla Luciferase Complementation Assay for the Evaluation of Hsp90/Aha1 Complex Disruptors and their Activity at the Aha1 C-Terminal Domain" 2023 ACS Chemical Biology, 18 (1), pp.184-192. DOI: 10.1021/acschembio.2c00854.
  • Mishra, S. J.; Reynolds, T. S.; Merfeld, T.; Balch, M.; Peng, S. X.; Deng, J. P.; Matts, R. and Blagg, B. "Structure-Activity Relationship Study of Tertiary Alcohol Hsp90?-Selective Inhibitors with Novel Binding Mode" 2022 ACS Medicinal Chemistry Letters, 13 (12), pp.1870-1878. DOI: 10.1021/acsmedchemlett.2c00327.
  • Rahmy, S.; Mishra, S. J.; Murphy, S.; Blagg, B. and Lu, X. "Hsp90 Beta Inhibition Upregulates Interferon Response and Enhances Immune Checkpoint Blockade Therapy in Murine Tumors" 2022 Frontiers in Immunology, 13, 1005045. DOI: 10.3389/fimmu.2022.1005045.