Thomas E. Smithgall, PhD

William S. McEllroy Professor and Chair


Dr. Smithgall

Contact

412-648-8106
Fax: 412-624-8997

530 Bridgeside Point II

450 Technology Drive

Pittsburgh, PA 15219

Education

PhD in Pharmacology, University of Pennsylvania School of Medicine

Research Summary

HIV-1 accessory proteins as new drug targets for AIDS. While current antiretroviral drugs have transformed HIV infection from a life-threatening illness to a chronic condition, they do not clear the virus from the patient and require life-long administration.  Chronic antiretroviral drug exposure can be toxic and promote drug resistance, underscoring the urgent need for new approaches to combat HIV.  We have discovered compounds that interfere with the functions of HIV-1 Nef as a new approach to antiretroviral therapy.  Unique to primate lentiviruses, Nef is critical for HIV-1 replication in vivo, immune escape of HIV-infected cells, and AIDS progression. Our small molecule HIV-1 Nef inhibitors potently suppress HIV replication and restore immune recognition of HIV-positive cells, raising the exciting possibility of their translational potential in new strategies to eliminate latent viral reservoirs.

Small molecule allosteric inhibitors of non-receptor tyrosine kinases. Protein-tyrosine kinases represent exciting drug targets for leukemia and many other cancers. Most current kinase inhibitors compete for ATP binding at the kinase domain active site. However, structural conservation of kinase active sites limits the clinical applications of ATP-competitive kinase inhibitors as well as their utility as chemical probes of individual kinase functions.  To address these issues, we are pursuing drug discovery strategies to find small molecules that enhance the natural allosteric mechanisms associated with kinase domain regulation.  Chemical library screening assays based on this concept are targeting members of the Src, Fes/Fps and Abl kinase families.  Allosteric inhibitors of these kinases are anticipated to have utility in the treatment of cancer and infectious diseases.

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Research Lab Affiliation

Publications

Shen, K., Moroco, J.A., Patel, R.K., Shi, H., Engen, J.R., Dorman, H.R. and Smithgall, T.E. The Src-family kinase Fgr is a transforming oncoprotein independent of SH3-SH2 domain regulation. Science Signaling 11: eaat5916, 2018. |  View Abstract

Weir, M.C., Shu, S.T., Patel, R.K., Hellwig, S.A., Chen, l., Tan, L., Gray, N.S. and Smithgall, T.E. Selective Inhibition of the Myeloid Src-Family Kinase Fgr Potently Suppresses AML Cell Growth in Vitro and in Vivo. ACS Chem. Biol. 13: 1551-1559, 2018. |  View Abstract

Moroco, J. A., Alvarado, J.J., Staudt, R.P., Wales, T.E., Smithgall, T.E., and Engen, J.R. Remodeling of HIV-1 Nef Structure by Src-Family Kinase Binding. J. Mol. Biol. 430: 310-321, 2018. |  View Abstract

Wu, M., Alvarado, J.J., Augelli-Szafran, C.E., Ptak, R.G., and Smithgall, T.E. A single β-octyl glucoside molecule induces HIV-1 Nef dimer formation in the absence of partner protein binding. PLoS ONE 13: e0192512, 2018. |  View Abstract

Mujib, S., A. Saiyed, S. Fadel, A. Bozorgzad, N. Aidarus, F. Y. Yue, E. Benko, C. Kovacs, L. Emert-Sedlak, T. E. Smithgall, and M. A. Ostrowski. Pharmacologic HIV-1 Nef blockade promotes CD8 T cell-mediated elimination of latently HIV-1-infected cells in vitro. J.Clin. Invest. Insight 2: e93684, 2017. |  View Abstract

Shu, S.T., Emert-Sedlak, L.A. and Smithgall, T.E. Cell-based fluorescence complementation reveals a role for HIV-1 Nef dimerization in AP-2 recruitment and CD4 downregulation. J. Biol. Chem. 292: 2670-2678, 2017. |  View Abstract

Weir, M.C., Hellwig, S.A., Tan, L., Liu, L., Gray, N.S. and Smithgall, T.E. Dual inhibition of Fes and Flt3 tyrosine kinases potently inhibits Flt3-ITD+ AML cell growth. PLoS ONE 12: e0181178, 2017. |  View Abstract