Thomas E. Smithgall, PhD
William S. McEllroy Professor and Chair
530 Bridgeside Point II
450 Technology Drive
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
Emert-Sedlak LA, Moukha-Chafiq O, Shi H, Du S, Alvarado JJ, Pathak V, Tanner SG, Hunter RN, Nebane M, Chen L, Ilina TV, Ishima R, Zhang S, Kuzmichev YV, Wonderlich ER, Schader SM, Augelli-Szafran CE, Ptak RG, and Smithgall TE. 2020. Inhibitors of HIV-1 Nef-Mediated Activation of the Myeloid Src-Family Kinase Hck Block HIV-1 Replication in Macrophages and Disrupt MHC-I Downregulation. ACS Infection. Dis. 8: 91-105. | View Abstract
Li WF, Aryal M, Shu ST and Smithgall TE. (2020) HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane. J Biol Chem. 295: 5163-5174. | View Abstract
Patel RK, Patel YK and Smithgall TE. 2020. In Vitro Evolution Reveals a Single Mutation as Sole Source of Src-Family Kinase C-Helix-out Inhibitor Resistance. ACS Chem Biol. 15: 2175–2184. | View Abstract
Shi H, Tice CM, Emert-Sedlak L, Chen L, Li WF, Carlsen M, Wrobel JE, Reitz AB and Smithgall TE. 2020. Tight-binding Hydroxypyrazole HIV-1 Nef Inhibitors Suppress Viral Replication in Donor Mononuclear Cells and Reverse Nef-mediated MHC-I downregulation. ACS Infectious Dis. 6: 302-312. [ePub ahead of print] | View Abstract
Staudt RP, Alvarado JJ, Emert-Sedlak LA, Shi H, Shu ST, Wales TE, Engen JR and Smithgall TE. 2020. Structure, function, and inhibitor targeting of HIV-1 Nef-effector kinase complexes. J Biol Chem. 295: 15158-15171. [ePub ahead of print] | 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
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
Youngner Lecture
Save the Date! Youngner Symposium -- May 3-4, 2023
