The Chemistry and Cancer Program seeks to discover “first in class” small molecule chemicals capable of either antagonizing or agonizing regulatory pathways relevant to human cancer. The research catalyzed by the Chemistry and Cancer Program directly couples the research of chemists with the skills and capabilities of biochemists, molecular biologists and geneticists.

The process of drug discovery involves the synthesis and identification of candidates, as well as their characterization, screening, and assays for therapeutic efficacy. For instance, Smac is normally a mitochondrial protein and is released into the cytosol only during apoptosis. Once in the cytoplasm, Smac binds to several Inhibitor of Apoptosis Proteins (IAPs) and neutralizes their ability to inhibit caspases, a group of intracellular proteases that execute apoptosis.

A group in the Biochemistry Department at UT Southwestern synthesized a potent mimic of Smac that outperforms the native protein in terms of relieving IAP inhibition of caspases (Science 2004, 305:1471). At subnanomolar concentrations, the Smac mimetic synergizes with death inducing cytokines such as TNF-α and TNF-related apoptosis-inducing ligand (TRAIL) to facilitate cell death in cancer cell lines that do not respond to these cytokines alone. The Smac mimetic has shown quite promising activity in vivo when administered in conjunction with TRAIL.

An onsite Cyclotron and Radiochemistry Facility is able to label the compounds developed by this group to enable PET imaging evaluation on the presence, efficacy, tissue distribution profile, pharmacodynamics, and pharmacokinetics of promising drug candidates.