Department of Pharmacology & Chemical Biology at the University of Pittsburgh
Thomas E. Smithgall, PhD
William S. McEllroy Professor of Biochemistry and Chair, Microbiology and Molecular Genetics
Suite 523, Bridgeside Point II, 450 Technology Drive
Pittsburgh, PA 15261

Email:
tsmithga@pitt.edu
Phone: 412-648-8106


Education

BA (Biochemistry) University of Pennsylvania, 1981.
PhD (Pharmacology) University of Pennsylvania, 1986.
Post-doc., National Cancer Institute, NIH, 1987-1991.



Research Areas
Cancer Pharmacology
Drug Discovery
Signal Transduction
Photo of Thomas E. Smithgall, PhD

HIV-1 accessory proteins as new drug targets for AIDS.  Treatment for HIV disease was revolutionized in the mid-1990’s with the advent of antiretroviral drugs, which inhibit viral enzymes as well as fusion of the virus to the host cell.  Unfortunately, existing antiretroviral therapy does not clear the virus from the body, requiring life-long drug administration to prevent relapse. The cumulative toxic effects of antiretroviral drug exposure over decades may cause clinical metabolic disturbances and organ damage. Chronic therapy also promotes drug resistance, ultimately limiting drug utility.  To address these issues, we are developing several classes of compounds that interfere with the functions of HIV-1 Nef, one of four viral accessory factors essential for HIV pathogenesis.  Nef, a small membrane-associated protein unique to primate lentiviruses, is critical for HIV-1 replication in vivo, immune escape of HIV-infected cells, and AIDS progression. Using our patented screening assays, we have identified HIV Nef inhibitors with potent antiretroviral activity against Nef-dependent HIV replication. Nef antagonists have the potential to synergize with current antiretroviral drugs, thereby lowering current doses and their associated toxicities and reducing the risk of drug resistance. Therapeutic inhibition of Nef may also restore recognition of HIV-infected cells by the patient’s own immune system, potentially eradicating the virus.

Discovery of small molecule allosteric inhibitors of non-receptor tyrosine kinases. In theory, inhibition of undesirable enzymatic activity responsible for disease can be accomplished either directly at the active site or indirectly at a distance (allostery). Important examples of selective enzyme inhibition come from the field of protein-tyrosine kinases, an emerging therapeutic target class for cancer and infectious diseases.  Virtually all clinically useful kinase inhibitors to date compete for ATP binding at the kinase domain active site. However, the high degree of protein kinase sequence and structural homology limits the development of highly selective ATP-competitive kinase inhibitors. Alternative drug discovery avenues include allosteric inhibitors that target structural features outside of the kinase domain active site that are unique to individual kinase subfamilies. Allosteric inhibitor mechanisms are likely to exhibit greater specificity for their intended kinase targets, and may also stabilize kinase domain conformations that promote the action of existing inhibitors targeting the active site. Based on these principles, we are actively engaged in a drug discovery campaign to find small molecules that enhance the natural allosteric mechanisms associated with kinase domain regulation. We have developed chemical library screening approaches based on this concept for the identification of selective inhibitors for protein-tyrosine kinases of the non-receptor class, including 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.




Important Publications
Emert-Sedlak, L.A., Narute, P., Shu, S.T., Poe, J.A., Shi, H., Yanamala, N., Alvarado, J.J., Lazo, J.S., Johnston, P.A., and Smithgall, T.E. Effector Kinase Coupling Enables High-Throughput Screens for Direct HIV-1 Nef Antagnoists with Anti-retroviral Activity. Chem. Biol. 20: 82-91, 2013.
Panjarian, S., Iacob, R.E., Chen, S., Engen, J.R., Smithgall, T.E. Structure and dynamic reguation of Abl kinases. J. Biol. Chem. 288: 5443-5450, 2013. (Review)
Panjarian, S., Iacob, R.E., Chen, S., Wales, T.E., Engen, J.R., Smithgall, T.E. Enhanced SH3:linker Interaction Overcomes Abl Kinase Activation by Gatekeeper and Myristic Acid Binding Pocket Mutations and Increases Sensitivity to Small Molecule Inhibitors. J. Biol. Chem. 288: 6119-6129, 2013.
Narute, P. and Smithgall, T.E. Nef Alleles from all major HIV-1 clades activate Src-family kinases and enhance HIV-1 replication in an inhibitor sensitive manner. PLoS ONE 7: e32561, 2012.
Hellwig, S., Miduturu, C.V., Kanda, S., Zhang, J., Filippakopoulous, P., Salah, E., Deng, X., Choi, H.G., Zhou, W., Hur, W., Knapp, S., Gray, N.S. and Smithgall, T.E. Small Molecule Inhibitors of the c-Fes Protein-tyrosine Kinase. Chem. Biol. 19: 529-40, 2012.
Pene-Dumitrescu, T.P. and Smithgall, T.E. Expression of a Src-Family Kinase in CML Cells Induces Resistance to Imatinib in a  Kinase-dependent Manner. J. Biol. Chem. 285: 21446-21457, 2010.
Poe, J.A. and Smithgall, T.E. Bimolecular Fluorescence Complimentation Reveals Residues Essential for HIV-1 Nef Oligomerization, CD4 Downregulation and Viral Replication. J. Mol. Biol. 394: 329-42, 2009.
Emert-Sedlak, L., Kodama, T., Lerner, E.C., Trible, R.P., Dai, W., Foster, C., Day, B., Lazo, J.S., and Smithgall, T.E. Chemical library screens targeting an HIV-1 Nef Accessory Factor/host cell kinase complex identify novel anti-retroviral compunds. ACS Chemical Biol. 4: 939-947, 2009.
Meyn III, M.A. and Smithgall, T.E. Chemical Genetics Identifies c-Src as an Activator of Primitive Ectoderm Formation in Murine Embryonic Stem Cells. Science Signaling 2 ra64, 2009.




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