My current and future research fuses chemical biology, immunology, cancer biology, biochemistry, and medicinal chemistry to discover and evaluate small molecule chemical probes that remodel the tumor-immune microenvironment. I implement the critical path for prioritization strategy to identify chemical probes that modulate recalcitrant transcription factors.
The critical path for prioritization begins with the small molecule microarray (SMM). This high-throughput approach utilizes small molecules functionalized on the surface, which then are fluorescently detected when bound by the screened protein. SMMs have surfaced as a robust and unbiased binding assay to identify multiple modes of small molecule-protein binders and is a great platform for rapidly discovering chemical tools. Once we've detected putative small molecule-protein binders (typically yielding 100s-1000s of compounds), transcriptional assays are typically used as a high-throughput cellular activity assay to obtain compounds that modulate the transcriptional function of the protein with single digit micromolar potency (typically yielding 10s of compounds). The compounds then go to a series of cellar assays to measure their affect of the desired cellular phenotype to prioritize hit compounds (typically yielding <10 compounds). Several target engagement strategies are then employed to determine if the compounds are acting on target to obtain two to three lead chemical series that can be studied more in depth. I will then focus on chemistry to establish structure activity relationships, early in vitro mechanistic studies, 'omics' studies including RNA-seq to map and track the reprogramming of the transcriptome upon compound treatment, and ultimately assess in vivo efficacy.