Keith C. Ellis, Ph.D.
Associate Professor
Department of Medicinal Chemistry
Faculty/Staff picture
  •   Virginia Biotechnology Research Park, Suite 205
  • School of Pharmacy - Dept of Medicinal Chemistry
    BioTech One, Suite 205
    800 E. Leigh St.
    Box 980540
    Richmond, VA 23298-0540
  •  (804) 828-4490
    (804) 828-7625

Area of Focus

  • Synthetic Medicinal Chemistry
  • Use of Natural Products as probes of biological activity
  • Identification of new anti-cancer targets
  • Elucidation of anti-cancer mechanisms of action
  • Discovery & Development of Anti-Infective Agents
  • Small Molecule Drug Discovery & Development
  • Discovery & Development of Anti-Cancer Agents
  • Natural Products as Drug Leads


  • Ph.D., Organic Chemistry (University of Virginia, 2004)
  • B.S., Chemistry (Cornell University, 1999)

Post-Graduate Training

  • Post-Doctoral Fellow - Medicinal Chemistry (University of Kansas, 2005)
  • Research Associate - Medicinal Chemistry (University of Minnesota, 2007)

Professional Experience

  • (2008 - Present) Assistant Professor, Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University
  • (2009 - Present) Associate Member, Massey Comprehensive Cancer Center, Virginia Commonwealth University,
  • (2009 - Present) Member, Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University
  • (2010 - Present) Affiliate Professor, Department of Chemistry, Virginia Commonwealth University

Research Interests

  • The Ellis Group conducts research at the interface of medicinal chemistry, organic synthesis, and chemical biology that investigates novel or unknown mechanisms of action, either chemical or biological. As part of these projects, we use organic synthesis to both develop new synthetic chemistry methodology and use known methodology to prepare novel molecules that will modulate biological systems in a desired way. We then use these molecules as chemical probes to examine the biological activity, identify the molecular target, and elucidate the mechanism of action. Once the molecular target and mechanism are known, we evaluate the SAR, prepare more potent analogs, develop new assays, screen chemical libraries for other scaffolds that interact with the new molecular target, and begin to evaluate the pharmacokinetics and pharmacodynamics.
  • Projects:
  • N-Chelation-directed C-H activation reactions catalyzed by heterogeneous palladium(II) on multi-walled carbon nanotubes [Pd(II)/MWCNT]
  • Chemical reactions that catalyze the selective conversion of unactivated C-H bonds to C-O, C-Halogen, C-C, C-N, C-F or C-CF3 are highly sought for their atom economy, cost savings, and synthetic utility and are in high demand in the pharmaceutical industry for the synthesis of Active Pharmaceutical Ingredients (APIs). One methodology to selectively carry out these transformations is oxidative N-chelation-directed reactions catalyzed by palladium in the +2 oxidation state (Pd(II)). However, the known methodology that utilizes homogeneous Pd(II) has limited utility to the pharmaceutical industry due to product contamination from residual palladium catalyst, which is difficult to effectively separate from the reaction product. To overcome this limitation, we have developed chemical transformations that uses a heterogeneous Pd(II) catalyst [Pd(II) on multi-walled carbon nanotubes, Pd(II)/MWCNT] to carry out N-chelation-directed C-H to C-O and C-Halogen transformations (see Organic Letters, 2015, 17(7), 1782-1785). The chemical transformations that we have developed demonstrated consistently higher turnover frequencies and shorter reaction times than the reported homogeneous catalyst. The heterogeneous Pd(II)/MWCNT also offers the advantages of ease of removal by filtration and low levels of residual palladium metal contamination in the products (<250 ppb). The catalyst can be recycled and reused in subsequent reactions. We have recently extended this transformation to use the heterogeneous Pd(II)/MWCNT catalyst to carry out N-chelation-directed C-H to C-C transformations.
  • Development of Activity-Based Probes for the AGC Kinases
  • Kinases of the AGC subfamily are critical regulators of multiple cell signaling pathways that control cell proliferation, migration, and apoptosis. Due to their importance in regulating cellular functions, the activation of AGC kinases themselves is tightly controlled and regulated by multiple mechanisms. Each AGC kinase is activated and regulated by post-translational modifications that include phosphorylation, disulfide bond formation, alkylation, and binding to regulatory proteins. Aberrant or uncontrolled activation of the AGC kinases occurs in a large percentage of cancers and is often the driving force in the cancer phenotype. Probe molecules that can quantitate the level of the activated form of a specific AGC kinase in vivo would be invaluable tools in studying the roles of these kinases in cancer. Activity-based protein profiling (ABPP) is a chemical proteomics strategy that can be used to selectively identify and quantify the activated form of a protein in cells of various phenotypes in vivo. ABPP requires the development of activity-based probes that meet three criteria: 1) the probes must covalently modify a residue in the target protein that is reactive only in the activated form of the protein; 2) the probes must contain a scaffold that binds selectively to the targeted enzyme family or single enzyme; and 3) the probes must contain a tag that can be used for isolation or detection. To date, only one activity-based probe has been reported for an AGC kinase (RSK). No activity-based probes have been reported for the other AGC kinases and no general strategy to develop these probes has been reported. Our goal is to develop a general strategy to prepare target-selective activity-based probes for AGC kinases.
  • Development of Inhibitors of C-Terminal Binding Protein (CtBP) as Tumor Selective Cancer Agents
  • (Collaboration with Steven R. Grossman, M.D., Ph.D., VCU Massey Cancer Center)
  • Several of the Hallmarks of Cancer, including tissue invasion and metastasis, sustained angiogenesis, and evading apoptosis, are driven by transcriptional repression of tumor suppressor genes. Repression of tumor suppressors such as BH3 proteins, PTEN, and E-cadherin results in an oncogenic phenotype that includes improper cell survival, cell migration, and cell invasion. C-terminal binding protein (CtBP) is an oncogenic transcriptional co-repressor of tumor suppressor genes that is overexpressed in the majority of colon, breast, and ovarian cancers (64%, 92%, and 83% of cases, respectively). CtBP overexpression leads to inappropriate cell survival as well as enhanced migratory and invasive properties, due to the ability of CtBP to repress transcription of the pro-apoptotic BH3 proteins, PTEN, and E-cadherin. Depletion of CtBP using siRNA in p53-/- HCT-116 cells results in a 2.6-fold increase in the expression of BH3 protein Bik and apoptosis, reversing the cancer phenotype. CtBP is a metabolic sensor and is activated as a co-repressor under conditions of hypoxia or glycolysis when NADH levels are elevated. CtBP contains a catalytically active dehydrogenase domain that binds NADH and the putative substrate, 4-methylthio-2-oxobutyric acid (MTOB). NADH binding induces dimerization and is necessary for transcriptional co-repression activity. The catalytic dehydrogenase activity of CtBP can be inhibited in vitro and in vivo in the presence of an excess of its substrate MTOB. MTOB inhibits recombinant CtBP dehydrogenase in vitro (IC50 = 300 µM), disrupts transcriptional repression, promotes the expression of the BH3 protein Bik in p53-/- HCT-116 cells, is specifically cytotoxic to both wild-type and p53-/- HCT-116 cells (GI50 = 4 mM) but not MEF cells in vitro, and has modest single agent activity and robust chemosensitizing activity in a p53-/- HCT-116 mouse xenograft model. We have discovered a new small molecule inhibitor of CtBP and are currently working to develop this lead into both a tool to study the role of CtBP in cancer and a potential therapeutic.


Recent Publications

  • 1. Marshall, J. A.; Ellis, K. C. “Total Synthesis of (-)- and (+)-Membrenone C.” Organic Letters. 2003, 5, 1729. PMID: 12735763
  • 2. Marshall, J. A.; Ellis, K. C. “Applications of chiral allenylzinc additions and Noyori asymmetric reductions to an enantioselective synthesis of a C3-C13 precursor of the polyketide phosphatase inhibitor cytostatin.” Tetrahedron Letters. 2004, 45, 1351.
  • 3. Marshall, J. A.; Yanik, M. M.; Adams, N. A.; Ellis, K. C.; Chobanian, H. R. “Generation of Nonracemic 2-(t-Butyldimethylsilyloxy)-3-Butynyllithium From (S)-Ethyl Lactate: (S)-4-(t-Butyldimethylsilyloxy)-2-Pentyn-1-ol.” Organic Synthesis. 2004, 81, 157.
  • 4. Kimball, F. Scott; Turunen, Brandon J.; Ellis, Keith C.; Georg, Gunda I.; Himes, Richard H. “Enantiospecific Synthesis and Cytotoxicity of 7-(4-Methoxyphenyl)-6-phenyl-2,3,8,8a-tetrahydroindolizin-5(1H)-one Enantiomers.” Bioorganic Medicinal Chemistry. 2008, 16, 4367. PMID: 18343127
  • 5. Sadiq, Ahad A.; Patel, Manish R.; Jacobson, Blake A.; Escobedo, Marco; Ellis, Keith C.; Oppegard, Lisa M.; Hiasa, Hiroshi; Kratzke, Robert A. “Anti-Proliferative Effects of Simocyclinone D8 (SD8), A Novel Inhibitor of Topoisomerase II.” Investigational New Drugs. Published on the web 01/09/2009. DOI 10.1007/s10637-008-9209-1. PMID: 19132295
  • 6. Oppegard, Lisa M.; Hamann, Bree L.; Streck, Kathryn R.; Ellis, Keith C.; Fiedler, Hans-Peter; Khodursky, Arkady B.; Hiasa, Hiroshi. “In vivo and in vitro patterns of the activity of simocyclinone D8, an angucyclinone antibiotic from Streptomyces antibioticus.” Antimicrobial Agents & Chemotherapeutics. 2009, 53(5), 2110-2119. PMID: 19273673
  • 7. Oppegard, Lisa M.; Nguyen, Thuy; Ellis, Keith C.; and Hiasa, Hiroshi. “Dual catalytic inhibition of human topoisomerases I and II by the antibiotic simocyclinone D8.” Journal of Natural Products. 2012, 75(8), 1485-89. DOI 10.1021/np300299y. PMID: 22867097.
  • 8. Verghese, Jenson; Nguyen, Thuy; Oppegard, Lisa M.; Hiasa, Hiroshi, and Ellis, Keith C. “Flavone-based analogues inspired by the natural product simocyclinone D8 as DNA gyrase inhibitors.” Bioorganic Medicinal Chemistry Letters. 2013, 23(21), 5874-5877. DOI: 10.1016/j.bmcl.2013.08.094 PMID: 24060488
  • 9. Korwar, Sudha; Nguyen, Thuy; and Ellis, Keith C. “Preparation and evaluation of deconstruction analogs of 7-deoxykalafungin as AKT kinase inhibitors.” Bioorganic Medicinal Chemistry Letters. 2014, 24(1), 271-274. DOI: 10.1016/j.bmcl.2013.11.020. PMID: 24321345
  • 10. Gaskell, Lauren; Nguyen, Thuy; and Ellis, Keith C. “Defining a minimum pharmacophore for simocyclinone D8 disruption of DNA gyrase binding to DNA.” Medicinal Chemistry Research. 2014, 23(8), 3632-3643. DOI 10.1007/s00044-014-0942-z.
  • 11. Nguyen, Thuy; Coover, Robert A.; Verghese, Jenson; Moran, Richard G.; and Ellis, Keith C. “Phenylalanine-Based Inactivator of AKT Kinase: Design, Synthesis, and Biological Evaluation.” ACS Medicinal Chemistry Letters. 2014, 5(5), 462-467. DOI: 10.1021/ml500088x. PMID: 24900862.
  • 12. Korwar S.; Brinkley K.; Siamaki A.R.; Gupton B.F.; Ellis K.C. “Selective N-chelation-directed C-H activation reactions catalyzed by Pd(II) nanoparticles supported on multiwalled carbon nanotubes.” Organic Letters 2015, 17(7), 1782-5. doi:10.1021/acs.orglett.5b00566. PMID: 25789562.
  • 13. Hilbert B.J.; Morris B.L.; Ellis K.C.; Paulsen J.L.; Schiffer C.A.; Grossman S.R. and Royer W.E. Jr. “Structure-Guided Design of a High Affinity Inhibitor to Human CtBP.” ACS Chemical Biology 2015, 10(4), 1118-27. doi: 10.1021/cb500820b. Epub 2015 Jan 30. PubMed PMID: 25636004.