Research TopicsDepartment of Chemistry; Affiliate in Biochemistry
Ph.D. (1999) University of Texas at Austin
Research Topics
Research Interests
The overarching goal of our research is to use small organic compounds to identify novel cellular targets that can be exploited in the treatment of diseases including cancer, neurodegeneration, and drug-resistant bacteria. The compounds used to validate these novel drug targets are identified through a variety of approaches, including natural product synthesis, combinatorial chemistry, structure-based design, and high-throughput screening. In the process, novel methods for the synthesis of various chemical building blocks and for biological assays often need to be developed. In addition, we work closely with the local medical community and perform tests directly on patient samples.
Novel anti-cancer targets. There are currently no treatments for certain cancers such as colon cancer and late-stage malignant melanoma. We have synthesized a series of compounds, the triphenylmethylamides (TPMAs), which powerfully induce programmed cell death in melanoma and are comparatively less toxic to non-cancerous cells. The TPMAs appear to function via a novel biochemical mechanism, and cause arrest of cancer cells in the G1 phase of the cell cycle. In a separate series of experiments, through high-throughput screening and combinatorial synthesis we have identified compounds that directly induce programmed cell death in a variety of cancer cells; these compounds are currently being tested against patient samples and in mouse models.
Novel targets for drug-resistant bacteria. Every year 90,000 people in the U.S. alone die from bacterial infections they acquire at hospitals. Many of these bacteria become resistant to antibiotics by taking up a plasmid, a small piece of circular DNA that encodes for the proteins that mediate antibiotic resistance. We have recently identified anti-plasmid agentscompounds that inhibit plasmid replication and thus sensitize bacteria to traditional antibiotics. We have focused sharply on Vancomycin-Resistant Enterococci (VRE); we have obtained clinical VRE isolates from local medical centers and are defining plasmid-encoded resistance in VRE. This work has spawned a large and general effort in the laboratory to develop a paradigm for small molecule-RNA binding. We have identified small molecule modules that bind tightly and specifically to defined regions of RNA secondary structure, including RNA hairpin loops and bulges. We are connecting such modules to target individual mRNAs in the cell with exquisite affinity and selectivity.
Key Words: Drug design, Combinational Chemistry, Biochemistry
Current Research Funding: National Institutes of Health, Office of Naval Research, National Science Foundation, Alfred P. Sloan Foundation, Arnold and Mabel Beckman foundation, Research Corporation, Michael J. Fox Foundation for Parkinson's Disease Research