Autophagy is a major catabolic recycling process that allows cells to maintain homeostasis. In cancer cells, autophagy promotes proliferation and tumorigenesis by facilitating cell survival within a hypoxic, nutrient-deprived environment, and thus, autophagy inhibition has emerged as a potential treatment strategy. While the FDA-approved anti-malarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been used in clinical trials to inhibit autophagy by disrupting lysosome function, they are not selective for the autophagy pathway and lead to off-target effects. Inhibition of kinases involved in autophagy initiation has emerged as a more selective method, and several inhibitors of the VPS34 lipid kinase have been developed. However, VSP34 is part of two multi-protein complexes, the autophagy initiation complex (Complex I) and the vesicle trafficking complex (Complex II), so direct inhibition of kinase activity will inhibit both pathways. In contrast, ATG14L is exclusively found in Complex I, where it interacts with Beclin 1 through a coiled-coil domain and recruits VPS15-VPS34 to the endoplasmic reticulum upon autophagy initiation. We recently optimized a cellular NanoBRET assay to monitor the interaction of the ATG14L-Beclin 1 protein-protein interaction and conducted a high-throughput screen to identify small molecules that inhibit this interaction. This led to the discovery of compound 19, which disrupts Complex I and selectively inhibits autophagy without impacting Complex II and vesicle trafficking. Synthetic strategies were developed to generate diverse analogues of this initial hit, and molecules with improved solubility have already been identified. Our current focus is the iterative synthesis and testing of analogues to improve the potency and properties of compound 19 to support <i>in vitro</i> and <i>in vivo</i> efficacy studies. These efficacy studies will help clarify the role of autophagy in cancer through selective inhibition of this pathway and will reveal the utility of autophagy inhibition as a potential therapeutic strategy in cancer.

Synthesis and optimization of ATG14L-beclin 1 protein-protein interaction inhibitors to selectively inhibit autophagy

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ACS Fall 2022

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