Chemistry at Illinois University of Illinois at Urbana-Champaign

John A. Katzenellenbogen

Research Professor of Chemistry
Affiliate of the Beckman Institute and
Department of Bioengineering

Professor John A. Katzenellenbogen attended Harvard University for his undergraduate and graduate work. He received his B.A. in 1966 and his Ph.D. in 1969, at which time he joined the faculty at Illinois. Professor Katzenellenbogen's research interests involve organic and inorganic chemistry, biochemistry, molecular biology, and radiochemistry.

Research

The action of steroid hormones is mediated by their binding to specific, high-affinity binding proteins that are found in target tissues only at very low concentrations and are a challenge to isolate and purify. We probe the molecular details of action of steroid hormones using chemical and spectroscopic tools and molecular biology to understand how these interesting proteins work and to develop novel medical diagnostic procedures. Many of our studies are done in collaboration with biologists.

Novel Ligands and Dendrimers.

Based on our models of receptor structure, we use organic synthesis and molecular biology to design ligands of novel structure and hormone-dendrimer conjugates in search of those having unusual biological activity and specificity. We co-engineer novel ligand-receptor pairs to obtain agents with unique, orthogonal specificity, useful in gene therapy and in separating genomic and non-genomic signaling pathways.

Receptor Structure and Protein Microarrays.

We develop novel spectroscopic methods to analyze receptor structure, conformation, and dynamics, and receptor-coregulator interactions, and how these are affected by ligand structure. We are using chemical and molecular biological methods to fabricate protein microarrays through which receptor ligand binding and coactivator interactions can be assayed in a quantitative and high throughput manner.

Combinatorial Chemistry.

Based on our analysis of the key structural features important for the receptor binding and activity of steroid hormones and anti-hormones, we have undertaken a combinatorial approach to discover novel non-steroidal hormonal agents. These compounds have important receptor subtype and tissue selectivity that could be useful for menopausal hormone replacement and breast and prostate cancer prevention and therapy.

Radiopharmaceuticals.

A novel approach to the diagnosis of breast and prostate cancer is the use of gamma- and positron-emitting steroids to label the receptors in these tumors. We are designing hormones labeled with the positron-emitting radionuclide fluorine-18. The designed steroids must maximize specific to nonspecific binding and control the level of metabolism. Also, because F-18 has a half-life of only 110 min, synthetic methods that are rapid, convenient, and efficient are required. We are also working to incorporate the radioactive metals technetium-99m and gallium-68 into structural mimics of steroids while maintaining high receptor binding and good bio-distribution properties.

Publications

M. Jeyakumar and J.A. Katzenellenbogen. A Dual-Acceptor Time-Resolved Foster Resonance Energy Transfer Assay for Simultaneous Determination of Thyroid Hormone Regulation of Corepressor and Coactivator Binding to the Thyroid Hormone Receptor: Mimicking the Cellular Context of Thyroid Hormone Action, Anal. Biochem., 2009, 386, 73-78. PMID: 19111515

J.R. Gunther, Y. Du, E. Rhoden, I. Lewis, B. Revennaugh, T.W. Moore, S.H. Kim, R. Dingledine, H. Fu, and J.A. Katzenellenbogen. A Set of Time-Resolved Fluorescence Resonance Energy Transfer Assays or the Discovery of Inhibitors of Estrogen Receptor-Coactivator Binding, J. Biomol. Screening, 2009, 14, 181-93. Pub Med Abstract PMC2731238

J.R. Gunther, A.A. Parent, J. A. Katzenellenbogen. Alternative Inhibition of Androgen Receptor Signaling: Peptidomimetic Pyrimidines as Direct Androgen Receptor/Coactivator Disruptors. ACS Chem. Biol. , 2009, 4, 435-440. Pub Med Abstract PMID: 19441848

A.L. LaFrate, K.E. Carlson, J. A. Katzenellenbogen. Steriodal Bivalent Ligands for the Estrogen Receptor: Design, Synthesis, Characterization and Binding Affinities. Bioorg. Med. Chem., 2009, 17, 3528-3535. Pub Med Abstract PMID: 19394231

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H. B. Zhou, K. W. Nettles, J. B. Bruning, Y. Kime, A. Joachimiak, S. Sharma, K. E. Carlson, F. Stossi, G. L. Greene, and J. A. Katzenellenbogen. Elemental Isomerism: A Boron-Nitrogen Surrogate for a Carbon-Carbon Double Bond Increases the Chemical Diversity of Estrogen Receptor Ligands.  Chem. Biol. 2007, 14, 659-669.

E. E. Parent, K. E. Carlson, J. A. Katzenellenbogen. Synthesis of 7alpha-(fluoromethyl)dihydrotestosterone and 7alpha-(fluoromethyl)nortestosterone, structurally paired androgens designed to probe the role of sex hormone binding globulin in imaging androgen receptors in prostate tumors by positron emission tomography. J. Org. Chem. 2007, 72, 5546-5554.

K. W. Nettles, J. B. Bruning, G. Gil, J. Nowak, S. K. Sharma, J. B. Hahm, K. Kulp, R. B. Hochberg, H. Zhou, J. A. Katzenellenbogen, B. S. Katzenellenbogen, Y. Kim, A. Joachmiak, G. L. Greene.  NFkB Selectivity of Estrogen Receptor Ligands Revealed by Comparative Crystallographic Analyses, Nature Chem. Bio. 2008, 4, 241-247.

J. R. Gunther, T.W. Moore, M.L. Collins, J.A. Katzenellenbogen.  Amphipathic Benzenes are Designed Inhibitors of the Estrogen Receptor Alpha/Steroid Receptor Coactivator Interaction, ACS Chem Bio, 2008, 5, 282-286.

E. E. Parent, C. S. Dence, Terry L. Sharp, M. J. Welch, J. A. Katzenellenbogen.  7α-[18F]Fluoromethyl-dihydrotestosterone and 7α-[18F]Fluoromethyl-nortestosterone: Ligands to Determine the Role of Sex Hormone Binding Globulin for Steroidal Radiopharmaceuticals, J. Nucl. Med., 2008 49, 987-994.

A. A. Parent, J. R. Gunther, and J. A. Katzenellenbogen.  Blocking Estrogen Signaling After the Hormone: Pyrimidine-Core Inhibitors of Estrogen Receptor-Binding, J. Med. Chem., 2008, 51, 6512-6530.

S. H. Kim, P. Ge, and J. A. Katzenellenbogen.  A New Quinoline Sensitizer-Centered Lanthanide Chelate and Its Use for Protein Labling on Ni-NTA Beads for TR LRET Assays.  Chem. Commun., 2009, 2, 183-185.

Awards

  • Philip S. Portoghese Medicinal Chemistry Lectureship Awardee, 2010
  • Leading Edge in Basic Science Award from the Society for Toxicology (SOT), 2009
  • RSC Centenary Lectureship, 2008
  • Gustavus John Esselen Award for Chemistry in the Public Interest, 2008
  • American Chemical Society E. B. Hershberg Award for Important Discoveries in Medicinally Active Products, 2007
  • Roy O. Greep Lecture Award, Endocrine Society
  • ACS Arthur C. Cope Scholar
  • Aebersold Award, Society of Nuclear Medicine
  • Fellow, American Academy of Arts & Sciences
  • Fellow, American Association for the Advancement of Science
  • Guggenheim Fellowhip
  • Dreyfus Fellowship
  • Alfred P. Sloan Fellowship

Highlights

Patents

Photo of John A. Katzenellenbogen