Chris Brosey, MD Anderson Cancer Center / Abbvie
SAXSi -- Integrating time-resolved and high-throughput small-angle X-ray scattering (TR-HT-SAXS) into drug discovery screening pipelines and inhibitor development.
Abstract:
Dynamic macromolecular conformations drive essential biological processes and provide attractive targets for controlling biomolecular function with chemical probes. For many drug discovery efforts, though, assessment of small-molecule impacts on relevant conformations remains secondary during initial hit identification. High-throughput small-angle X-ray scattering (HT-SAXS) is well positioned to profile biomolecular states and transitions as part of hit identification, allowing discovery efforts to accelerate chemical matter tailored to mechanistically important structural states. To this end, we have developed a conformational small-molecule discovery pipeline integrating time-resolved HT-SAXS (TR-HT-SAXS) and classic fragment screening and applied it to allosteric redox states of the mitochondrial import factor apoptosis-inducing factor (AIF). By monitoring oxidized and X-ray-reduced AIF states, TR-HT-SAXS leverages both structure and kinetics to generate a multidimensional screening dataset, identifying fragment chemotypes which allosterically stimulate AIF dimerization. Moreover, quantification of fragment-induced dimerization rates using the time-resolved SAXS similarity metric kVR captures key structure–activity relationships (SAR) across the top-ranked 4-aminoquinoline chemotype. This TR-HT-SAXS framework provides a resource to leverage conformational selection in small-molecule discovery efforts and a general opportunity for multiplexed characterization of X-ray-responsive structural dynamics in biological systems.
Speaker: Chris Brosey, MD Anderson Cancer Center / Abbvie
Dr. Brosey is currently a member of the Structural Biology team at Abbvie, supporting structure-based drug design in therapeutic areas of oncology, immunology, and neuroscience. She additionally leads efforts to develop workflows for applying small-angle X-ray scattering (SAXS) to target characterization and small-molecule screening. Dr. Brosey completed her Ph.D. at Vanderbilt University in the laboratory of Dr. Walter Chazin, specializing in NMR and SAXS analysis of DNA processing machinery. She subsequently pursued postdoctoral training in X-ray crystallography with Dr. Tom Ellenberger at Washington University School of Medicine in St. Louis. Following this, Dr. Brosey joined the newly established laboratory of Dr. John Tainer at MD Anderson Cancer Center in Houston, where she developed approaches to integrate SAXS into discovery pipelines for chemical probes, supported structure-based drug design of inhibitors for the DNA damage signaling enzyme poly(ADP-ribose) glycohydrolase, and continued her research on the allosteric regulation of the AIF/CHCHD4 mitochondrial import pathway. Her current research interests include redox-regulated protein allostery, regulation of mitochondrial protein import, and applications of SAXS in drug discovery.
Host: Kwaku Dayie
Seminars start at 4:00 pm, and refreshments will be served at 3:45 pm. All seminars are held in the Conference Room (1116) of the Institute for Physical Science and Technology (IPST) Building (Bldg #085) unless otherwise noted.