Research & Collaborations

The Warren Center for Drug Discovery is a collaborative program well aligned with the University’s overarching Catholic mission through its focus on the discovery and development of new therapeutic leads for the treatment of unmet clinical needs in a number of areas including cancer, infectious diseases, and a number of rare diseases. The Center brings together chemical and biological expertise and technologies through partnerships with researchers within the University’s biomedical research centers at the, including the Harper Cancer Institute, the Eck Institute for Global Health, the Center for Rare and Neglected Disease, and external partners, including regional universities and the Indiana CTSI, Eli Lilly, Inc. and other pharmaceutical companies as well as private foundations including the Ara Parseghian Medical Research Foundation and the Grace Science Foundation.

 

Recent examples include

  • Professors Paul Helquist and Olaf Wiest collaborated on an active component in the treatment of Niemann-Pick C1 disease. Davidson, J.; Molitor, E.; Moores, S.; Gale, S.; Subramanian, K.; Jiang, X.; Sidhu, R.; Kell, P.; Zhang, J.; Fujiwara, H.; Davidson, C.; Helquist, P.; Melancon, B.; Grigalunas, M.; Liu, G.; Salahi, F.; Wiest, O.; Xu, X.; Porter, F. D.; Pipalia, N. H.; Cruz, D. L.; Holson, E. B.; Schaffer, J. E.; Walkley, S. U.; Maxfield, F. R.; Ory, D. S. “2-Hydroxypropyl-β-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 disease” Biochim .Biophys. Acta. Mol. Cell Biol. Lipids 20191864, 1545–1561. PMID:31051283. DOI:10.1016/j.bbalip.2019.04.011https://doi.org/10.1016/j.bbalip.2019.04.011

 

  • Professors  Mayland Chang and Brandon Ashfeld revealed ribosomal targeting spirooxindole cyclopropanes through their collobaration. Rodriguez, K.X.; Howe, E.N.; Bacher, E.P.; Burnette, M.; Meloche, J.L.; Meisel, J.; Schnepp, P.; Tan, X.; Chang, M.; Zartman, J.; Zhang, S.’ Ashfeld, B.L. Combined scaffold evaluation and systems-level transcriptome-based analysis for accelerated lead optimization reveals ribosomal targeting spirooxindole cyclopropanes. ChemMedChem 2019, 14, 1653-1661.

 

  • Professors Mayland Chang, Matthew Champion and Shahriar Mobashery joint efforts validated MMP-9 as a novel target for treatment of diabetic foot ulcers and discovered a new inhibitor that accelerates healing.  Nguyen, T.T.; Ding, D.; Wolter, W. R.; Pérez, R. L.; Champion, M. M.; Mahasenan, K. V.; Desek, D.; Lee, M.; Schroeder, V. A.; Jones, J. R.; Lastochkin, E.; Rose, M. K.; Peterson, C. E.; Suckow, M. A.; Mobashery, S.; Chang, M. Validation of matrix metalloproteinase (MMP)-9 as a novel target for treatment of diabetic foot ulcers in humans and discovery of a potent and selective small-molecule MMP-9 inhibitor that accelerates healing. J. Med. Chem. 2018, 61, 8825-8837.

 

  • Prof. Shahriar Mobashery and his team documented that transglycosylase Slt turns over the peptidoglycan by both exolytic and endolytic reactions causing glycosidic bond scission from a terminus or in the middle of the peptidoglycan, respectively. Lee, M.; Batuecas, M. T.; Tomoshige, S.; Domínguez-Gil, T.; Mahasenan, K. V.; Dik, D. A.; Hesek, D.; Millán, C.; Usón, I.; Lastochkin, E.; Hermoso, J. A.; Mobashery, S. “Exolytic and endolytic turnover of peptidoglycan by lytic transglycosylase Slt of Pseudomonas aeruginosa,”Proc. Natl. Acad. Sci. USA 2018, 115(17), 4393-4398. DOI: 10.1073/pnas.1801298115.

 

  • Prof. Richard E. Taylor and his team describe the synthesis of neopeltolide and its 2-methyl-substituted analogue. Through computer modeling and NMR studies, the analogue was shown to maintain the conformational preferences of its biologically active parent compound. Both compounds inhibited mitochondrial respiration of P. falciparum parasites demonstrating their potential as antimalarial compounds. Larsen, E. M.; Chang, C. F.; Sakata-Kato, T.; Arico, J. W.; Lombardo, V. M.; Wirth, D. F.; Taylor, R. E. “Conformation-guided analogue design identifies potential antimalarial compounds through inhibition of mitochondrial respiration,” Org. Biomol. Chem. 201816(30), 5403-5406. DOI: 10.1039/c8ob01257a.

 

  • Chemistry & Biochemistry Dept. Chair, Prof. Brian M. Baker and his team demonstrated new principles of T cell receptor cross-reactivity, implicating new paradigms to predict and control T cell specificity and cross-reactivity. They also highlighted challenges associated with predicting T cell reactivities. Riley, T. P.; Hellman, L. M.; Gee, M. H.; Mendoza, J. L.; Alonso, J. A.; Foley, K. C.; Nishimura, M. I.; Vander Kooi, C. W.; Garcia, K. C.; Baker, B. M. “T cell receptor cross-reactivity expanded by dramatic peptide-MHC adaptability,” Nature Chem. Biol. 201814(10), 934-942. DOI: 10.1038/s41589-018-0130-4.

 

  • Center researchers, Prof. Brandon Ashfeld and Prof. Siyuan Zhang illustrated that epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth. Schnepp, P.M.; Lee, D.D.; Guldner, I. H.; O'Tighearnaigh, T. K.; Howe, E. N.; Palakurthi, B.; Eckert, K. E.; Toni, T. A.; Ashfeld, B. L.; Zhang, S “GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment,” Cancer Res. 201777(11), 2844-2856. DOI: 10.1158/0008-5472.CAN-16-2289

 

  • Center Director Brian Blagg and BSD Core Director John Koren showed that Aha1 contributes to tau fibril formation and neurotoxicity through Hsp90, suggesting that therapeutics targeting Aha1 may reduce toxic tau oligomers and slow or prevent neurodegenerative disease progression. Shelton, L. B.; Baker, J. D.; Zheng, D.; Sullivan, L. E.; Solanki, P. K.; Webster, J. M.; Sun, Z.; Sabbagh, J. J.; Nordhues, B. A.; Koren, J. III; Ghosh, S.; Blagg, B. S. J.; Blair, L. J.; Dickey, C. A. “Hsp90 activator Aha1 drives production of pathological tau aggregates,” Proc. Natl. Acad. Sci. USA 2017, 114(36), 9707-9712. DOI: 10.1073/pnas.1707039114.