Chemical Biology Strategies for Targeting Transcriptional Axes in Neurological Disorders

Abstract

Transcriptional dysregulation is a hallmark of numerous neurological disorders, offering targetable pathways with the potential to alter disease progression substantially. This Dissertation integrates chemical biology and precision medicine principles to discover and characterize small molecules capable of modulating dysregulated pathways. Through a series of functional cell-based screening assays targeting key transcriptional axes, such as the Wnt signaling pathway, AP-1 transcription factors, and BET family members, this work identifies compounds that exhibit unexpected, often gain-of-function, mechanisms of action. These discoveries, which include potential therapeutics for neurological and neuropsychiatric disorders, highlight transcriptional vulnerabilities that would not have been attainable through genetic or in vitro screening alone. Building on these discoveries, we validated the therapeutic potential of these compounds through their characterization in patient-derived induced pluripotent stem cell models. This work begins with the discovery of small molecules that reprogram BET family members for the enhancement of GRN (Chapter 2) and extends these investigations into a microglia-like cell type aided by the development of a microglia- based PGRN-luciferase reporter line (Chapter 3). I next turn towards the discovery of a class of 3,5-disubstituted isoxazole carboxamides that can enhance Wnt signaling and describe our target identification efforts that converge on RNA-binding proteins (Chapter 4). Finally, I detail the characterization of covalent modifiers of the transcription factor ΔFosB and introduce a novel reporter line that aids in the discovery of small molecule AP-1 modulators (Chapter 5). Collectively, my studies demonstrate the utility of chemical biology approaches in identifying therapeutically relevant small molecules with unexpected mechanisms of action and highlight their potential within precision medicine frameworks.