John T. Koh, Professor
University of Delaware
273 Brown Lab
Newark, DE 19716
(b. 1967) B.S., 1989, West Chester University; M.S., 1990, Columbia University; Ph.D., 1994 Columbia University; American Cancer Society Postdoctoral Fellow, 1994 – 1996, University of California Berkeley
We are interested in designing and synthesizing new molecules for applications in biomedical discovery. Our goal is not to simply make known molecules, but to design and create new molecules novel functions. Using a variety of techniques including computeraided molecular design, organic synthesis as well techniques from molecular and cell biology, we can create new approaches to the treatment of cancer and disease.
Molecular Rescue of Genetic Mutations
Much of our current research projects involve a family of proteins called the nuclear and steroid hormone receptors. These receptors regulate the expression of specific genes upon binding non-peptide hormones such as estrogen, vitamin D and thyroid hormone. Much of the details by which these molecular systems control gene expression have recently been revealed by high-resolution molecular structures that allow us to design hormone analogs with unique properties.
Mutant forms of hormone receptors are associated with a family of human genetic diseases such as rickets, resistance to thyroid hormone (RTH), cushing’s disease as well as certain forms of diabetes, breast cancer and prostate cancer. Many of these mutations occur in and around the hormone-binding pocket of the protein and affect the ability of the hormone to properly regulate the expression of hormone-responsive genes. Although these mutant receptors no longer respond to their natural hormones, we have been able to successfully design and synthesize hormone analogs that are capable of restoring activity to these otherwise functionally impaired proteins associated with rickets and RTH. These studies represent the first examples of molecules that have been designed to rescue function to mutant proteins associated with a human genetic disease. Recently we have begun to direct our molecular rescue strategy towards androgen receptor and thyroid hormone receptor mutations that are associated with a variety of human cancers.
Through a combination of sitedirected mutagenesis and chemical synthesis, we have created a series of highly selective ligandreceptor pairs that can be used to selectively and independently regulate the expression of target genes in cells. Such tools may help us understand the many complex functions mediated by nuclear receptors and may also serve as unique tools to control the expression of transgenes used in future gene therapies.
patiotemporal Control of Gene Expression
Many gene products, critical to development, elicit their effects through their unique spatial and temporal patterns of expression. Such systems are extremely difficult to study by our current methods. Using a combined chemical-genetic approach, we have generated a set of photo-responsive hormone analogs that can uniquely control the expression of genes in response to light. This unique tool allows us to regulate the expression of genes in both time and space. Through collaboration with neurobiologists, we are investigating the application of such tools to the study the effects of spatial patterns of cell surface proteins that guide axons during development. Chemists are unique in their ability to understand and manipulate molecular structure. The availability of high resolution structures of biological macromolecules provides us with new and exciting opportunities use design and synthesis to address important biomedical problems.
- A. Q. Hassan and J. T. Koh “Selective chemical rescue of a thyroid-hormone-receptor mutant, TR beta(H435Y), identified in pituitary carcinoma and resistance to thyroid hormone,” Angewandte Chemie, 47, 7280 – 7283.
- P. L. McGinley and J. T. Koh “Circumventing Anti-Androgen Resistance by Molecular Design,” J. Am. Chem. Soc., (2007) 129, 3822 – 3823.
- A. Q. Hassan and J. T. Koh “A Functionally Orthogonal Ligand-Receptor Pair Created by Targeting the Allostertic Mechanism of the Thyroid Hormone Receptor,” J. Am. Chem. Soc., (2006) 126, 8868 – 8874.
- J. F. Zheng, A. Hashimoto, M. Putnam, K. Miller and J. T. Koh “Development of a thyroid hormone receptor targeting conjugate,” Bioconjugate Chemistry, (2008) 19, 1227 – 1234.
- K. Link, Y. Shi and J. T. Koh “Light-Activated Recombination,” J. Am. Chem Soc., (2005) 127, 13088 – 13089.
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