Something Borrowed, Something New: Drug Discovery Approaches in Chemical Biology
Posted October 16, 2009
A September 9, 2009, meeting of the Academy's Chemical Biology Discussion Group showcased a variety of ways to identify small molecules that hold potential as new drugs; namely, rational molecular design, natural products, and chemical libraries. John Koh explained how rational drug design can be used to create ligands that restore function to mutated nuclear hormone receptors. Akira Kawamura described efforts to isolate the active compounds from two traditional Asian herbal medicines. Using gene chip expression analysis and fractionation techniques, his group has identified important molecules found in Toki-shakuyaku-san (TSS) and Juzen-taiho-to (JTT). Tom Kodadek presented a general approach for identifying immunobiomarkers for any disease to which the immune system reacts in a specific fashion. Using synthetic mimics of protein antigens called peptoids in an EAE mouse model of multiple sclerosis, he has had preliminary success in preventing stimulation of autoimmune T cell proliferation.
Use the tabs above to find a meeting report and multimedia from this event.
Biggins JB, Koh JT. 2007. Chemical biology of steroid and nuclear hormone receptors. Curr. Opin. Chem. Biol. 11: 99-110.
Biggins JB, Hashimoto A, Koh JT. 2007. Photocaged agonist for an analogue-specific form of the vitamin D receptor. Chembiochem. 8: 799-803.
Bohl CE, Gao W, Miller DD, et al. 2005. Structural basis for antagonism and resistance of bicalutamide in prostate cancer. Proc. Natl. Acad. Sci. USA 102: 6201-6206. (PDF, 715 KB) Full Text
Hassan AQ, Koh JT. 2008. Selective chemical rescue of a thyroid-hormone-receptor mutant, TRbeta(H435Y), identified in pituitary carcinoma and resistance to thyroid hormone. Angew. Chem. Int. Ed. Engl. 47: 7280-7283.
Koh JT, Zheng J. 2007. The new biomimetic chemistry: artificial transcription factors. ACS Chem. Biol. 2: 599-601.
McGinley PL, Koh JT. 2007. Circumventing anti-androgen resistance by molecular design. J. Am. Chem. Soc. 129: 3822-3823. Full Text
Posner GH, Suh BC, Petersen KS, et al. 2007. Difluoromethyl analogs of the natural hormone 1alpha,25-dihydroxyvitamin D3: Design, synthesis, and preliminary biological evaluation. J. Steroid Biochem. Mol. Biol. 103: 213-221. Full Text
Zheng J, Hashimoto A, Putnam M, et al. 2008. Development of a thyroid hormone receptor targeting conjugate. Bioconjug. Chem. 19: 1227-1234.
Baur JA, Sinclair DA. 2006. Therapeutic potential of resveratrol: the in vivo evidence. Nat. Rev. Drug Discov. 5: 493-506.
Kawamura A, Brekman A, Grigoryev Y, et al. 2006. Rediscovery of natural products using genomic tools. Bioorg. Med. Chem. Lett. 16: 2846-2849.
Kawamura A, Iacovidou M, Takaoka A, et al. 2007. A polyacetylene compound from herbal medicine regulates genes associated with thrombosis in endothelial cells. Bioorg. Med. Chem. Lett. 17: 6879-6882. Full Text
Lavie CJ, Milani RV, Mehra MR, Ventura HO. 2009. Omega-3 polyunsaturated fatty acids and cardiovascular diseases. J. Am. Coll. Cardiol. 54: 585-594.
Saiki I. 2000. A Kampo medicine "Juzen-taiho-to"—prevention of malignant progression and metastasis of tumor cells and the mechanism of action. Biol. Pharm. Bull. 23: 677-688.
Kwon Y, Kodadek T. 2008. Encoded combinatorial libraries for the construction of cyclic peptoid microarrays. Chem. Commun. (Camb.) Nov 30(44): 5704-5706.
Lee J, Yu P, Xiao X, Kodadek T. 2008. A general system for evaluating the efficiency of chromophore-assisted light inactivation (CALI) of proteins reveals Ru(II) tris-bipyridyl as an unusually efficient "warhead". Mol. Biosyst. 4: 59-65.
Lim H, Reddy MM, Xiao X, et al. 2009. Rapid identification of improved protein ligands using peptoid microarrays. Bioorg. Med. Chem. Lett. 19: 3866-3869.
Marthandan N, Klyza S, Li S, et al. 2008. Construction and evaluation of an automated light directed protein-detecting microarray synthesizer. IEEE Trans Nanobioscience 7: 20-27.
Tan NC, Yu P, Kwon Y, Kodadek T. 2008. High-throughput evaluation of relative cell permeability between peptoids and peptides. Bioorg. Med. Chem. 16: 5853-5861. Full Text
Zuckermann RN, Kodadek T. 2009. Peptoids as potential therapeutics. Curr. Opin. Mol. Ther. 11: 299-307.
Juzen-taiho-to (Shi-Quan-Da-Bu-Tang): Scientific Evaluation and Clinical Applications (Traditional Herbal Medicines for Modern Times, V. 5), Eds. Yamada, H. and Saiki, I, 2005, CRC Press , Hardcover, 256 pages.
John T. Koh, PhD
John Koh received his PhD with Ronald Breslow at Columbia University, where he studied biomimetic organic catalysts of pyridoxal enzyme mimics. As an American Cancer Society postdoctoral fellow working in the labs of Peter Schultz, he developed combinatorial libraries of kinase inhibitors and studied protein stability using unnatural amino-acid mutagenesis. Koh started his independent career at the University of Delaware in 1996 where he developed a program to apply structure-based molecular design to the development of nuclear receptor ligands. The Koh lab developed the first mutant-selective hormone analogs for remote regulation of gene expression, the first light-activated transactivation system based on small molecules, and the first example of a small molecule designed to rescue function to mutant receptors associated with a genetic disease. Currently the Koh group has projects involving the estrogen, androgen, and thyroid hormone action. Koh is the associate director of the Delaware Biotechnology Institute and serves on the editorial board of Molecular Biosystems.
Akira Kawamura, PhD
Akira Kawamura was born in Japan. He received his BS and MS at the University of Tokyo and his PhD at Columbia University with Koji Nakanishi, followed by a postdoctoral stint at the Scripps Research Institute with Peter Schultz. He is currently an associate professor of chemistry at Hunter College of CUNY. His research interest is bioorganic and natural products chemistry.
Thomas J. Kodadek, PhD
Thomas Kodadek received his BS in chemistry from the University of Miami in 1981 and a PhD in organic chemistry from Stanford University in 1985 under the direction of James Collman and John Brauman. He performed postdoctoral studies in biochemistry and molecular biology with Bruce Alberts at the University of California, San Francisco from 1985–1987. He was on the faculty of the Department of Chemistry and Biochemistry at the University of Texas at Austin from 1987–1997. He moved to the UT Southwestern Medical Center in Dallas and was professor of internal medicine and molecular biology from 1998–2009 and director of the Division of Translational Research from 2006–2009. In June 2009 he moved to his present position as professor of chemistry & cancer biology at the Scripps Research Institute, Scripps Florida. His laboratory studies a variety of biological problems with direct implications in human health. These projects employ a wide range of techniques form molecular genetics to organic synthesis. In 2006, Kodadek was awarded an NIH Director's Pioneer Award to support his work.
Jamie Kass is a web editor at the Academy. She holds a PhD in genetics.