Chemical Profiling Reveals Epigenetic Control of
T Cell Activation
I am a doctoral trainee working with Dr. Drew Adams. The Adams lab has a unique position in the department where we leverage chemical insights and synthetic chemistry techniques to (i) discover novel drug targets across a broad range of diseases, (ii) delineate therapeutic mechanisms and articulate novel biological phenomena, and (iii) translate our findings towards clinical applications through a strong relationship with the Small Molecule Drug Development core facility. My thesis project, with support from the Harrington Discovery Institute, aims to develop next generation therapies for autoimmune and inflammatory diseases. Tens of millions of patients in the United States alone are affected by one of more than one hundred autoimmune diseases, and clinical data suggests that the prevalence of these diseases will increase with time. Current treatment strategies rely on global immunosuppression that are plagued by variable efficacy and debilitating side effects. Therefore, new therapies for the immunological space remain in high demand.
Previous high-throughput small molecule screens precipitated covalent inhibitors that display strong selectivity for T cell function over other immune cell lineages with minimal cytotoxicity. Using click chemistry-mediated proteomic profiling, we discovered that these inhibitors exert their therapeutic effects through a shared antineoplastic target. This finding led us to describe multiple series of small molecule inhibitors that exhibit divergent cellular activity profiles in vitro and in vivo through the same molecular target. Moreover, we used novel epigenetic techniques to demonstrate that their effects on T cell function are achieved through a poorly documented non-canonical function. Our results articulate a new mechanism through which cells regulate their transcriptional landscape and establish a paradigm whereby the same molecular target can be indicated for diverse pathologies. Through an interdisciplinary effort spanning synthetic chemistry, structural biology, epigenetics, and immunology, our team is using multiple –omics technologies to investigate mechanisms that govern T cell transcription while creating a pipeline to accelerate our translational efforts.
Two structurally distinct small molecules share the same molecular target and achieve distinct cellular activities.