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 15219-3143

Education

PhD in Pharmacology, University of Pennsylvania School of Medicine

Research Summary

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 anticipate to have utility in the treatment of cancer and infectious diseases.

 

Chemical genetics of Src-family kinases in ES cells. This project involves the role of Src-family kinases in the early fate determination of murine and human embryonic stem (ES) cells.  Remarkably both human and mouse ES cells express almost all Src-family members, suggesting that each kinase may serve unique roles in the regulation of ES renewal and differentiation.  We have developed a chemical genetics approach to investigate the contributions of individual kinases in this cell type.  This involves Src kinases with engineered resistance to broad-spectrum ATP-site inhibitors of the entire Src family.  Using this method, we discovered a specific role for c-Src in the transition of ES cells to primitive ectoderm and endoderm, one of the earliest steps in differentiation. In marked contrast, we found that c-Yes opposes this effect of c-Src and promotes self-renewal, even though these two kinases share a close phylogenetic relationship. Ultimately, we hope to identify small molecules with Src-family kinase selectivity profiles to promote either ES cell renewal or guide desired developmental fates.

 

Research Lab Affiliation

Publications

Zhang X, Meyn M.A., 3rd and Smithgall, T.E. (2014) c-Yes tyrosine kinase is a potent suppressor of ES cell differentiation and antagonizes the actions of its closest phylogenetic relative, c-Src. ACS Chem Biol. 9: 139-146. |  View Abstract

Poe J.A., Vollmer L, Vogt A and Smithgall, T.E. (2014) Development and validation of a high-content bimolecular fluorescence complementation assay for small-molecule inhibitors of HIV-1 Nef dimerization. J Biomol Screen. 19: 556-565. |  View Abstract

Tarafdar S, Poe J.A. and Smithgall, T.E. (2014) The accessory factor Nef links HIV-1 to Tec/Btk kinases in an Src homology 3 domain-dependent manner. J Biol Chem. 289:15718-15728. |  View Abstract

Moroco J.A., Craigo J.K., Iacob R.E., Wales T.E., Engen J.R. and Smithgall, T.E. (2014) Differential sensitivity of Src-family kinases to activation by SH3 domain displacement. PLoS One. 9: e105629. |  View Abstract

Alvarado J.J., Tarafdar S, Yeh J.I. and Smithgall, T.E. (2014) Interaction with the Src Homology (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

Zhang X, Simerly C, Hartnett C, Schatten G and Smithgall, T.E. (2014) Src-family tyrosine kinase activities are essential for differentiation of human embryonic stem cells. Stem Cell Res. 13: 379-389. |  View Abstract

Panjarian S, Iacob R. E, Chen S, Wales T. E, Engen J. R, and Smithgall T. E. (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