Development and Optimization of Disease-Relevant Autophagy Modulators and Bioactive Libraries

Autophagy is a major catabolic degradation and recycling process that enables cells to maintain homeostasis. This process has been implicated in a variety of different disease states such as cancer and Alzheimer's disease, and autophagy modulation has emerged as a potential therapeutic strategy in these cases. These projects implement high-throughput screens to discover small-molecule autophagy modulators to serve as a starting point for synthetic optimization of potency and properties. The development of selective inhibitors of the ATG14L-Beclin 1 protein-protein interaction through a target-based approach offers a novel method to inhibit autophagy in cancer where this pathway is utilized for proliferation and chemotherapeutic resistance. In contrast, a phenotypic approach and subsequent target identification studies have enabled the discovery of autophagy modulators with novel biological targets which could be especially impactful for the treatment of neurodegenerative diseases due to limited clinical success of current strategies. In both cases, synthetic modifications driven by iterative evaluation of analogues to develop structure-activity relationships have provided compounds with improved potency and pharmacokinetic properties. These approaches will help to clarify the role small-molecule autophagy modulation has in cancer and Alzheimer's disease and what critical chemical features are necessary when developing high-throughput, disease-relevant screens to ultimately give the best chance of therapeutic success. Additional work seeks to improve high-throughput screening campaigns by addressing which chemical features within a screening library are important for biological performance diversity. Libraries possessing performance diversity will increase efficacy while minimizing redundant activity, improving hit rates and leading more efficient screening campaigns.