Organic Chemistry Seminar
The Lairson laboratory uses chemical biology-based approaches, involving cell-based phenotypic screening coupled to target identification and mechanism of action studies, to investigate cell fate- and cell state-determining processes that play causative roles in human disease biology. Research is primarily focused on applying this approach to study remyelination and cGAS-STING pathway signal transduction, as well as to target glioblastoma cancer stem cells in a cell type-selective manner. Remyelination-inducing agents have significant potential utility in the treatment of demyelinating diseases, including progressive forms of multiple sclerosis. Using a cell-based imaging assay involving primary optic nerve-derived progenitor cells, a drug class was identified that induces oligodendrocyte differentiation and enhances remyelination in rodent models. A representative member from this drug class was subsequently demonstrated to meet a remyelination-based endpoint in a phase 2 clinical trial conducted by investigators at UCSF. Current efforts in this area, involving pairwise combinatorial drug screening, have built on these findings and resulted in new mechanistic hypotheses for future clinical investigation. cGAS-STING signal transduction plays an essential role in innate responses to infection or pathogenic sources of self-DNA. Pharmacological activators or inhibitors of this pathway have diverse potential applications in diseases ranging from cancer to inflammation. Using a pathway-targeted cell-based screening approach, small molecules with demonstrated in vivo activity have been identified that function not only by acting as direct agonists of STING adaptor function, but also as pathway-specific modulators that function via newly identified targets. Finally, glioblastoma cancer stem cells (GBM CSCs) have been demonstrated to be responsible for tumor initiation, metastasis, therapy resistance and recurrence following surgical resection. Cell-based screening involving primary GBM CSCs resulted in the identification of a chemical series that induces cell death in GBM CSCs in a cell type-selective manner. Cell type selectivity was determined to be derived at least in part from the ability of the series to act as a prodrug that becomes preferentially activated in the target cell population to yield a cytotoxic agent. Very recently, it has been demonstrated that this prodrug strategy can be applied to significantly enhance the selectivity profile of a clinical stage drug, which yielded a GBM-selective cytotoxic derivative with low nM potency and demonstrated in vivo activity in an orthotopic tumor xenograft model.