Structure–Activity Relationship Studies of an Autophagy Inhibitor That Targets the ATG14L-Beclin1 Protein–Protein Interaction Reveal Modifications That Improve Potency and Solubility and Maintain Selectivity

Autophagy, a recycling process in eukaryotes, contributes to tumor growth and metastasis by alleviating cellular stress and facilitating survival and chemoresistance. The development of small molecules that selectively inhibit this pathway has proven challenging and is required to determine if autophagy inhibition can be harnessed as an effective therapeutic strategy in cancer. Compound 19 was previously identified as a selective autophagy inhibitor that targets the ATG14L-Beclin1 protein–protein interaction, which regulates the formation, localization, and function of VPS34 Complex I to initiate autophagy. Importantly, Compound 19 does not inhibit the UVRAG-Beclin1 protein–protein interaction in VPS34 Complex II that regulates vesicle trafficking, thus overcoming a major limitation of targeting VPS34 lipid kinase activity. Subsequent development of strategies to synthesize Compound 19 analogues has enabled the evaluation of structure–activity relationships, revealing key regions and moieties that impact the properties of Compound 19 and impart selectivity for VPS34 Complex I over Complex II.