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

Mujib S, Saiyed A, Fadel S, Bozorgzad A, Aidarus N, Yue FY, Benko E, Kovacs C, Emert-Sedlak L, Smithgall TE and Ostrowski MA. 2017. Pharmacologic HIV-1 Nef Blockade Enhances the Recognition and Elimination of Latency HIV-1 Infected CD4 T cells by Autologous CD8 T cells. J Clin Invest Insight. 2: e93684. |  View Abstract

Alvarado JJ, Tarafdar S and Smithgall TE. 2014. Interaction with the SH3-SH2 region of the Src-family kinase Hck structures the HIV-1 Nef dimer for kinase activation and effector recruitment. J Biol Chem. 289: 28539-28553. |  View Abstract

Panjarian S, Iacob RE, Chen S, Wales TE, Engen JR, and Smithgall TE. 2013. 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: 6116-6129. |  View Abstract

Emert-Sedlak LA, Narute P, Shu ST, Poe JA, Shi H, Yanamala N, Alvarado JJ, Lazo JS, Yeh JI, Johnston PA and Smithgall TE. 2013. Effector kinase coupling enables high-throughput screens for direct HIV-1 Nef antagonists with antiretroviral activity. Chem Biol. 20: 82-91. |  View Abstract

Meyn III, MA and Smithgall TE. 2009. Chemical genetics identifies c-Src as an activator of primitive ectoderm formation in murine embryonic stem cells. Sci Signal. 2: ra64. Cover Feature. Podcast available. Cited ‘Must Read’ by the Faculty of 1000/Biology. |  View Abstract