Cancer lead discovery and lead optimization is a particular focus in the Webb laboratory. The major research program encompasses a new area of medicinal chemistry; novel inhibitors of the spliceosome that are based on a natural product pharmacophore as lead compounds for multiple cancer types. Additionally we are actively pursuing the development of chemical biology tools for the elucidation of the widely used, but poorly understood, schistosomiasis drug, Praziquantel. Our laboratory also has ongoing research in the development of cheminformatics and molecular modeling tools for the applied de novo design of ligands and new combinatorial templates based on pharmacophore information.
The Webb laboratory has initiated work around the establishment of the structure-activity relationships (SAR) of compounds based on the natural product FR 901416. This natural product appears to act via a novel mechanism that involves transcriptional modulation by inhibition of the spliceosome. A series of novel analogs have been designed using insights into the pharmacophore of this molecule that is key to its biological activity. The goal of this project will be to understand the SAR requirements of these analogs, of FR 901464, and to develop safe lead compounds for tumor types that are most vulnerable to these agents.
The Webb laboratory has recently initiated a multi-site collaboration to elucidate the mechanism of action of the widely used anthelmintic drug praziquantel. PZQ is the drug of choice for the treatment of all known forms of human schistosomiasis. There are thought to be at least 250 million people infected with this disease, primarily in tropical climates. Resistance to PZQ is expected to develop into a significant problem in the future, making an improved understanding of its precise mode of action an important issue in human health. The Webb laboratory is developing the synthesis of modified PZQ analogs; new affinity labels related to PZQ as well as radio-labeled PZQ analogs, to use as tools to delineate the molecular target of PZQ with collaborators at the University of New Mexico.
As Director of High Throughput Chemistry (HTC) in the Chemical Biology and Therapeutics (CBT) Department at St. Jude Children’s Research Hospital, Dr. Webb leads a team that designs and prepares novel compound libraries, which target the numerous disease areas of interest to SJCRH researchers and their collaborators. Webb has previously developed computational methods and designed kinase inhibitor libraries that have led to compounds active in animal models of human cancer, so one future line of work with be on the refinement of these methods, as well as the development of new technology of this type by their application to ongoing research projects. The resulting refined techniques will also be applied to the numerous research projects that will be supported by St. Jude’s CBT HTC core facility. Another aspect of the Webb laboratory ongoing research will be the continued development and application of de novo ligand and template methods that have been pioneered in the Webb laboratory. Additionally the above efforts are complemented by an ongoing interest in the application of the most advanced work in organic synthesis and compound analysis and purification via application of enantioselective and diastereoselective synthesis and chiral supercritical fluid chromatography (SFC), respectively.