Group Leader, Chemistry NIH Chemical Genomics Center Education Ph.D. Syracuse University Contact (301) 217-5733 craigt@mail.nih.gov NIH Chemical Genomics Center 9800 Medical Center Drive Rockville, MD 20850

The research interests of the NCGC chemistry team are focus on the design, synthesis and understanding of small molecules that perturb a specific biochemical process or phenotype. Foremost at the NCGC are the amplification and optimization of small molecule actives that are revealed within the qHTS paradigm of the NCGC screening center. We have initiated a system where libraries of compounds (typically no larger than 50 molecules) are always purified and fully characterized prior to biochemical evaluation. We achieve this through employing the latest in technologies that include multiple prep-LC and prep-LCMS systems. Through this methodology we are able to advance novel, biochemically active compounds typically from 6-8 rotations of synthesis and evaluation. Current efforts on probe optimization projects include 1) A series of triazines with potent inhibitory potential of glucocerebrosidase, 2) A series of pthalimide based inhibitors of AmpC, 3) A series of substituted oxadiazoles that are potent inhibitors of PRX, 4) A series of substituted quinazolin analogues with the ability to affect gene splicing. Beyond these efforts are enterprises aimed at the design of molecular tools through ‘rational’ methods. We are currently advancing small molecules aimed at 1) Novel probes of small molecule/macromolecule binding, 2) Novel chemical libraries and natural product synthesis 3) Fragment and structural based ligand optimization 4) small molecule approaches to overcoming multidrug resistance 5) small molecule tools directed at elucidating glycosylidation pathways.

Recent Publications:

• Skoumbourdis, A. P.; LeClair, C. A.; Stefan, E.; Turjanski, A. G.; Maguire, W.; Titus, S. A.; Huang, R.; Auld, D. S.; Inglese, J.; Austin, C. P.; Michnick, S. W.; Xia, M.; Thomas, C. J.; Exploration and Optimization of Substituted Triazolothiadiazines and Triazolopyridazines as PDE4 Inhibitors. Bioorg. Med. Chem. Lett. accepted
• Auld, D. S.; Zhang, Y.-Q.; Southall, N. T.; Rai, G.; Landsman, M.; MacLure, J.; Langevin, D.; Thomas, C. J.; Austin , C. P.; Inglese, J. A Basis for Reduced Chemical Library Inhibition of Firefly Luciferase Obtained from Directed Evolution. J. Med. Chem. accepted.
• Rai, G.; Thomas, C. J.; Leister, W.; Maloney, D. J. Synthesis of Oxadiazole-2-oxide Analogues as Potential Antischistosomal Agents. Tett. Lett. accepted.
• Jiang, J-k.; Ghoreschi, K.; Deflorian, F.; Chen, Z.; Perreira, M.; Pesu, M.; Smith, J.; Nguyen, D.-T.; Liu, E. H.; Leister, W.; Costanzi, S.; O’Shea, J. J.; Thomas, C. J. Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550). (2008) J. Med Chem. 51, 8012-8018.
• Dolle, R. E.; Le Bourdonnec, B.; Goodmann, A. J.; Morales, G. A.; Thomas, C. J.; Zhang, W. Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology : 2007. (2008) J. Comb. Chem. 10, 753–802
• Neumann, S.; Kleinau, G.; Costanzi, S.; Moore, S.; Jiang, J-k.; Raaka, B. M.; Thomas, C. J.; Krause, G.; Gershengorn, M. C. A Low Molecular Weight Antagonist for the Human Thyrotropin Receptor with Therapeutic Potential for Hyperthyroidism. (2008) Endocrinology 149, 5945-5950.
• Marinello, J.; Marchand, C.; Mott, B. T.; Bain, A.; Thomas, C. J.; Pommier, Y. Comparison of Raltegravir and Elvitegravir on HIV-1 Integrase Catalytic Reactions and on a Series of Drug-Resistant Integrase Mutants. (2008) Biochemistry 47, 9345–9354
• Readinger, J. A.; Schiralli, G. M.; Jiang, J.-K.; Thomas, C. J.; August, A.; Henderson, A. J.; Schwartzberg, P. L. Selective Targeting of ITK blocks multiple steps of HIV Replication. (2008) Proc. Nat. Acad. Sci. 105, 6684-6689.
• Engel, S.; Skoumbourdis, A. P.; Childress, J. ; Neumann, S.; Deschamps, J. R.; Thomas, C. J.; Colson A.-O.; Costanzi, S.; Gershengorn, M. C. A Virtual Screen for Diverse Ligands: Discovery of Selective G Protein-Coupled Receptor Antagonists. (2008) J. Am. Chem. Soc. 130, 5115-5123.
• Bhanu, N. V.; Lee, Y. T. ; Oneal, P.A. ; Gantt, N. M.; Aerbajinai, W.; Noel, P.; Thomas, C. J.; Miller, J. L. Inhibition of erythroblast growth and fetal hemoglobin production by ribofuranose-substituted adenosine derivative. (2008) Biochemica et Biophysica Acta. 1782, 540-510.
• Babaoglu, K.; Simeonov, A.; Irwin, J.; Nelson, M.; Feng, B. Y.; Thomas, C. J.; Cancian, L.; Costi, M. P.; Maltby, D.; Jadhav, A.; Inglese, J.; Austin, C. P.; Shoichet, B. K. A Comprehensive Mechanistic Analysis of Hits from High-Throughput and Docking Screens Against Beta-Lactamase. (2008) J. Med. Chem. 51, 2502-2511.
• Sayed, A. A.; Simeonov, A.; Thomas, C. J.; Inglese, J.; Austin, C. P.; Williams, D. L. Identification of oxadiazoles as new drug leads for the control of schistosomiasis. (2008) Nature Med. 14, 407-412.
• Simeonov, A., Jadhav, A., Thomas, C. J., Wang, Y., Huang, R., Southall, N., Shin., P., Smith, J., Austin, C. P., Auld, D. S., Inglese, J. Fluorescence Spectroscopic Profiling of Compound Libraries. (2008) J. Med. Chem. 51, 2363-2371.
• Skoumbourdis, A. P., Huang, R., Southall, N., Leister, W., Guo, V., Cho, M.-H., Inglese, J., Nirenberg, M., Austin, C. P., Xia, M., Thomas, C. J. Identification of a Potent New Chemotype for the Selective Inhibition of PDE4. (2008) Bioorg. Med. Chem. Lett. 18, 1297-1303.
• Xie, Y., Deng, S., Thomas, C. J., Liu, Y., Zhang, Y.-Q., Rinderspacher, A., Huang, W., Gong, G., Wyler, M., Cayanis, E., Aulner, N., Tobben, U., Chung, C., Pompou, S., Southall, N., Vidovic, D., Schurer, S., Branden, L., Davis, R. E., Staudt, L. M., Inglese, J., Austin, C. P., Landry, D. W., Smith, D. H., Auld, D. S. Identification of N-(quinolin-8-yl)benzenesulfonamides as agents capable of down-regulating NFkB activity within two separate high-throughput screens of NKkB activation. (2008) Bioorg. Med. Chem. Lett. 18, 329-335.
• Zhang, X.-H., Loprieato, J. A., Hong, J. A., Kang, Y., Zhao, M., Chen, G.-Z., Chen, G. A., Humphries, A., Thomas, C. J., Trepel, J. B., Nguyen, D. M., Rao, M., Yu, X., Schrump, D. S. Depsipeptide FK228 Inhibits Aurora Kinase Expression and Induces Mitotic Catastrophe in Lung Cancer Cells, (2007) J. Clin. Cancer Res. Submitted.
• Tikhonova, I. G., Shing, S. C., Neumann, S., Thomas, C. J., Raaka, B. M., Costanzi, S., Gershengorn, M. C. A bi-directional, iterative approach to the structural delineation of the functional "chemoprint" in GPR40 for agonist recognition. (2007) J. Med. Chem. accepted.
• Arimondo, P. B., Thomas, C. J., Oussedik, K., Baldeyrou, B., Mahieu, C., Halby, L., Guianvarc’h, D., Lansiaux, A., Hecht, S. M., Bailly, C., Giovannangeli, C. Exploring the Cellular Activity of Camptothecin-Triple-Helix-Forming Oligonucleotide Conjugates. (2006). Mol. Cell. Biol. 26, 324-333.
• Kim, E.-J., Perreira, M., Thomas, C. J., Hanover, J. A. An O-GlcNAcase-Specific Inhibitor and Substrate Engineered by the Extension of the N-Acetyl Moiety. (2006). J. Am. Chem. Soc. 128, 4234-4235.
• Thomas, C. J. Fluorinated Natural Products with Clinical Significance. (2006) Curr. Top. Med. Chem. 6, 1529-1543.
• Moore, S., Jaeschke, H., Kleinau, G., Neumann, S., Costanzi, S., Jiang, J.-k., Childress, J., Raaka, B. M., Colson, A., Paschke, R., Krause, G., Thomas, C. J., Gershengorn, M. C. Evaluation of Small-Molecule Modulators of the Luteinizing Hormone/Choriogonadotropin and Thryroid Stimulating Hormone Receptors: Structure-Activity Relationships and Selective Binding Patterns. (2006) J. Med. Chem. 49, 3888-3896.

Chemistry at the NIH Chemical Genomics Center: