Thomas Smithgall, PhD

  • Chair, Department of Microbiology and Molecular Genetics
  • William S. McEllroy Professor of Biochemistry

Education & Training

  • Graduate School – University of Pennsylvania – PhD - Pharmacology

Research Grants

NIH Grants:  R01

Research Summary

Dr. Smithgall’s research is centered on drug discovery related to HIV/AIDS and cancer.  While 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.  The Smithgall group has discovered small molecules that block the functions of the HIV-1 Nef virulence factor.  These compounds 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.  Non-receptor 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, the Smithgall laboratory is pursuing drug discovery strategies to find small molecules that enhance the natural allosteric mechanisms associated with kinase regulation.  Promising drug candidates have been identified with potential clinical utility in acute myelogenous leukemia, either as stand-alone drugs or in combination with existing ATP-site inhibitors.

Representative Publications

  1. Shen K, Moroco JA, Patel RK, Shi H, Engen JR, Dorman HR, Smithgall TE. The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation. Sci Signal. 2018 Oct 23;11(553). pii: eaat5916. doi: 10.1126/scisignal.aat5916. PubMed PMID: 30352950.
  2. Weir MC, Shu ST, Patel RK, Hellwig S, Chen L, Tan L, Gray NS, Smithgall TE. Selective Inhibition of the Myeloid Src-Family Kinase Fgr Potently Suppresses AML Cell Growth in Vitro and in Vivo. ACS Chem Biol. 2018 Jun 15;13(6):1551-1559. doi: 10.1021/acschembio.8b00154. Epub 2018 May 30. PubMed PMID: 29763550; PubMed Central PMCID: PMC6130198.
  3. Shi J, Xiong R, Zhou T, Su P, Zhang X, Qiu X, Li H, Li S, Yu C, Wang B, Ding C, Smithgall TE, Zheng YH. HIV-1 Nef Antagonizes SERINC5 Restriction by Downregulation of SERINC5 via the Endosome/Lysosome System. J Virol. 2018 May 14;92(11). pii: e00196-18. doi: 10.1128/JVI.00196-18. Print 2018 Jun 1. PubMed PMID: 29514909; PubMed Central PMCID: PMC5952139.
  4. Wu M, Alvarado JJ, Augelli-Szafran CE, Ptak RG, Smithgall TE. A single β-octyl glucoside molecule induces HIV-1 Nef dimer formation in the absence of partner protein binding. PLoS One. 2018 Feb 7;13(2):e0192512. doi: 10.1371/journal.pone.0192512. eCollection 2018. Erratum in: PLoS One. 2018 Apr 17;13(4):e0196229. PubMed PMID: 29415006; PubMed Central PMCID: PMC5802939.
  5. Moroco JA, Alvarado JJ, Staudt RP, Shi H, Wales TE, Smithgall TE, Engen JR. Remodeling of HIV-1 Nef Structure by Src-Family Kinase Binding. J Mol Biol. 2018 Feb 2;430(3):310-321. doi: 10.1016/j.jmb.2017.12.008. Epub 2017 Dec 16. PubMed PMID: 29258818; PubMed Central PMCID: PMC5801098.
  6. Mujib S, Saiyed A, Fadel S, Bozorgzad A, Aidarus N, Yue FY, Benko E, Kovacs C, Emert-Sedlak LA, Smithgall TE, Ostrowski MA. Pharmacologic HIV-1 Nef blockade promotes CD8 T cell-mediated elimination of latently HIV-1-infected cells in vitro. JCI Insight. 2017 Sep 7;2(17). pii: 93684. doi: 10.1172/jci.insight.93684. [Epub ahead of print] PubMed PMID: 28878119; PubMed Central PMCID: PMC5621880 
  7. Advani G, Lim YC, Catimel B, Lio DSS, Ng NLY, Chüeh AC, Tran M, Anasir MI, Verkade H, Zhu HJ, Turk BE, Smithgall TE, Ang CS, Griffin M, Cheng HC. Csk-homologous kinase (Chk) is an efficient inhibitor of Src-family kinases but a poor catalyst of phosphorylation of their C-terminal regulatory tyrosine. Cell Commun Signal. 2017 Aug 7;15(1):29. doi: 10.1186/s12964-017-0186-x. PubMed PMID: 28784162; PubMed Central PMCID: PMC5547543.
  8. Weir MC, Hellwig S, Tan L, Liu Y, Gray NS, Smithgall TE. Dual inhibition of Fes and Flt3 tyrosine kinases potently inhibits Flt3-ITD+ AML cell growth. PLoS One. 2017 Jul 20;12(7):e0181178. doi: 10.1371/journal.pone.0181178. eCollection 2017. PubMed PMID: 28727840; PubMed Central PMCID: PMC5519068.