Student Hosted Colloquia: Dennis Wolan, Genentech

"New approaches for lead molecule optimization"

Host: Franco Faucher

About the Seminar

Lead optimization is a significant hurdle in the drug and probe development process due to the costly amounts of consumables, labor expenses and time, and reliance on the synthetic skills of medicinal chemists. Critically, a majority of academic labs do not have access to medicinal chemistry and often use low-quality chemical probes that may provide misleading results. The design of a universal and cost-effective HT structure-activity relationship (SAR) lead optimization platform is therefore a significant priority. In addition, biocompatible chemistries that would permit the direct measurement of products in any assay system without purification would be a tremendous benefit to improving the throughput of the medicinal chemistry process. We have recently repurposed sulfur(VI) fluoride exchange (SuFEx) reactions between iminosulfur oxydifluoride (“isodifluor”)-containing molecules and amines that yield >90% of the desired product in DMSO and PBS. Our studies show that we can synthesize SuFEx-enabled SAR libraries from an isodifluor-containing lead molecule on picomole scale, directly assess the products with in vitro assays, and discover inhibitors with significantly improved potency against a collection of diverse biomedically relevant protein targets. We anticipate our methodology can accelerate the development of robust biological probes and drug candidates.

About the Speaker

Dennis received his Ph.D. from The Scripps Research Institute in X-ray crystallography structure-based drug design and performed his postdoctoral research at the University of California, San Francisco in small molecule discovery. He returned to Scripps as a Principal Investigator and his group’s research focused on the development and application of chemical probes to understand protease biology, as well as the roles that distal gut commensal microbiome bacterial proteins play in human health and disease. Dennis recently moved his lab to Genentech, Inc. where the team continues to design and apply general and specific small molecule irreversible probes in combination with mass spectrometry proteomics to survey for aberrant protein functions in gastrointestinal diseases. Ultimately, the specific regulation of these identified disease-associated enzymes by chemical and/or biological interventions will provide critical insights into the influence target proteins have in disease phenotypes.