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Research Interests: Drug discovery focused on the TGF-beta signaling pathway Smad proteins in pancreatic cancer, diabetic nephropathy and muscular dystrophy.

Research Description: The TGF-beta signal transduction pathway plays key roles in normal functions such as wound healing and suppression of the immune system.  But TGF-beta signaling has also been implicated as a factor in cancer, as a causative agent in all fibrotic diseases including diabetic nephropathy and as an exacerbating factor in muscle weakness in muscular dystrophy.  In human tumors, such as pancreatic tumors, the normal growth inhibitory function of TGF-beta is lost.  In some advanced tumors, the pathway is altered such that TGF-beta stimulates proliferation of the cancer cell.  TGF-beta also promotes tumor growth and spread by enhancing cell migration, angiogeness, immune suppression and stromal activation.

The Smad proteins and several Smad-interacting transcription factors provide an array of new targets that could be potential sites for therapeutic intervention. There are currently no therapeutic agents that act on these targets in the TGF-beta pathway.

Our working hypothesis is that inhibition of specific Smad protein-protein interactions will selectively attenuate certain cellular responses to TGF-beta, e.g., inhibit fibrosis but maintain cell proliferation control and immunosuppression by TGF-beta.

We are using a genetic approach to define protein binding hotspots on the surfaces of Smad proteins and characterizing the affects of missense mutations in the hot spots on Smad protein binding and on Smad function in Smad-deficient cells. 

We have established high throughput screening (HTS) assays, secondary assays and counter screens for over twenty Smad protein-protein interactions.  These assays have been validated using peptide ligands binding to Smads.  We are currently screening chemical libraries at the UW-Madison Small Molecule Screening Facility.

My interests in academic drug discovery have also led to collaborative projects with other UW-Madison faculty through my role as faculty supervisor of the Small Molecule Screening Facility.

Selected recent publications

Ewald, J. A., Peters, N., Desotelle, J. A., Hoffmann, F. M., and Jarrard, D. F.  A High-Throughput Method to Identify Novel Senescence-Inducing Compounds.  J. Biomol. Screen., 14: 853-858, 2009.

Ju, J., Li, W., Yuan, Q., Peters, N. R., Hoffmann, F. M., Rajski, S. R., Osada, H., and Shen, B.  Functional Characterization of ttmM Unveils New Tautomycin Analogs and Insight into Tautomycin Biosynthesis and Activity.  Org. Lett., 11:  1639-1642, 2009.

Ju, J., Rajski, S. R., Lim, S.-K., Seo, J.-W., Peters, N. R., Hoffmann, F. M., and Shen, B.  Lactimidomycin, Iso-migrastatin and Related Glutarimide-containing 12-membered Macrolides are Extremely Potent Inhibitors of Cell Migration.  J. Am. Chem. Soc., 131:  1370-1371, 2009.

Hoffmann, F. M., Cui, Q., Lim, S. K., and Zhao, B. M.  Targeting Smad-dependent TGF-β Signaling with Peptide Aptamers.  In:  S. B. Jakowlew (Ed.), Transforming Growth Factor-β in Cancer Therapy, Volume II, Chapter 45.  Totowa, NJ:  Humana Press, 2008.

Ju, J., Rajski, S. R., Lim, S.-K., Seo, J.-W., Peters, N. R., Hoffmann, F. M., and Shen, B.  Evaluation of New Migrastatin and Dorrigocin Congeners Unveils Cell Migration Inhibitors with Dramatically Improved Potency.  Bioorg. Med. Chem. Lett., 18:  5951-5954, 2008.

Trubetskoy, O. V., Finel, M., Kurkela, M., Fitzgerald, M., Peters, N. R., Hoffmann, F. M., and Trubetskoy, V. S.  High Throughput Screening Assay for UDP-Glucuronosyltransferase 1A1 Glucuronidation Profiling.  Assay Drug Dev. Technol., 5:  343-354, 2007.

Yang, B., O’Herrin, S. M., Wu, J., Reagan-Shaw, S., Ma, Y., Bhat, K. M. R., Gravekamp, C., Setaluri, V., Peters, N., Hoffmann, F. M., Peng, H., Ivanov, A. V., Simpson, A. J. G., and Longley, B. J.  MAGE-A, mMage-b, and MAGE-C Proteins Form Complexes with KAP1 and Suppress p53-Dependent Apoptosis in MAGE-Positive Cell Lines.  Cancer Res., 67:  9954-9962, 2007.

Ahmed, A., Peters, N. R., Fitzgerald, M. K., Watson, J. A. Jr., Hoffmann, F. M., and Thorson, J. S.  Colchicine Glycorandomization Influences Cytotoxicity and Mechanism of Action.  J. Am. Chem. Soc., 128:  14224-14225, 2006.

Lim, S. K., and Hoffmann, F. M.  Smad4 Cooperates with Lymphoid Enhancer-binding Factor 1/T Cell-specific Factor to Increase c-myc Expression in the Absence of TGF-β Signaling.  Proc. Natl. Acad. Sci. USA, 103:  18580-18585, 2006.

Zhao, B. M., and Hoffmann, F. M.  Inhibition of Transforming Growth Factor-β1-induced Signaling and Epithelial-to-Mesenchymal Transition by the Smad-binding Peptide Aptamer Trx-SARA.  Mol. Biol. Cell, 17:  3819-3831, 2006.

Cui, Q., Lim, S. K., Zhao, B., and Hoffmann, F. M. Selective Inhibition of TGF-β Responsive Genes by Smad-interacting Peptide Aptamers from FoxH1, Lef1 and CBP. Oncogene, 24: 3864-3874, 2005.

Langenhan, J. M., Peters, N. R., Guzei, I. A., Hoffmann, F. M., and Thorson, J. S. Enhancing the Anticancer Properties of Cardiac Glycosides by Neoglycorandomization. Proc. Natl. Acad. Sci. USA, 102: 12305-12310, 2005.

Martin, M., Ahern-Djamali, S. M., Hoffmann, F. M., and Saxton, W. M. Abl Tyrosine Kinase and Its Substrate Ena/VASP Have Functional Interactions with Kinesin-1. Mol. Biol. Cell, 16: 4225-4230, 2005.

Ahern-Djamali, S. M., Bachmann, C., Hua, P., Reddy, S. K., Kastenmeier, A. S., Walter, U., and Hoffmann, F. M. Identification of Profilin and src Homology 3 Domains as Binding Partners for Drosophila enabled. Proc. Natl. Acad. Sci. USA, 96: 4977-4982, 1999.

Fogarty, F. J., Juang, J.-L., Petersen, J., Clark, M. J., Hoffmann, F. M., and Mosher, D. F. Dominant Effects of the bcr-abl Oncogene on Drosophila Morphogenesis. Oncogene, 18: 219-232, 1999.

Johnson, K., Kirkpatrick, H., Comer, A., Hoffmann, F. M., and Laughon, A. Interactions of Smad Complexes with Tripartite DNA-binding Sites. J. Biol. Chem., 274: 20709-20716, 1999.

Juang, J.-L., and Hoffmann, F. M. Drosophila Abelson Interacting Protein (dAbi) Is a Positive Regulator of Abelson Tyrosine Kinase Activity. Oncogene, 18: 5138-5147, 1999.

Ahern-Djamali, S. M., Comer, A. R., Bachmann, C., Kastenmeier, A. S., Reddy, S. K., Beckerle, M. C., Walter, U., and Hoffmann, F. M. Mutations in Drosophila Enabled and Rescue by Human Vasodilator-stimulated Phosphoprotein (VASP) Indicate Important Functional Roles for Ena/VASP Homology Domain 1 (EVH1) and EVH2 Domains. Mol. Biol. Cell, 9: 2157-2171, 1998.

Chen, Y., Riese, M. J., Killinger, M. A., and Hoffmann, F. M. A Genetic Screen for Modifiers of Drosophila decapentaplegic Signaling Identifies Mutations in punt, Mothers against dpp and the BMP-7 Homologue, 60A. Development, 125: 1759-1768, 1998.

Comer, A. R., Ahern-Djamali, S. M., Juang, J.-L., Jackson, P. D., and Hoffmann, F. M. Phosphorylation of Enabled by the Drosophila Abelson Tyrosine Kinase Regulates the in Vivo Function and Protein-Protein Interactions of Enabled. Mol. Cell. Biol., 18: 152-160, 1998.

Horsfield, J., Penton, A., Secombe, J., Hoffmann, F. M., and Richardson, H. decapentaplegic Is Required for Arrest in G1 Phase during Drosophila Eye Development. Development, 125: 5069-5078, 1998.