Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo.

摘要: UNC-51-like kinase 1 (ULK1) is well-known to initiate autophagy, and the downregulation of ULK1 has been found in most breast cancer tissues. Thus, activation ULK1-modulated autophagy could be a promising strategy for therapy. In this study, we that was remarkably downregulated tissue samples by The Cancer Genome Atlas (TCGA) analysis microarray (TMA) analysis, especially triple negative (TNBC). To design agonist, integrated silico screening chemical synthesis acquire series small molecule candidates. After rounds anti-proliferative activity screening, discovered molecule, LYN-1604, best candidate agonist. Additionally, identified three amino acid residues (LYS50, LEU53, TYR89) were key site LYN-1604 site-directed mutagenesis biochemical assays. Subsequently, demonstrated induce cell death, associated with ULK complex (ULK1-mATG13-FIP200-ATG101) MDA-MB-231 cells. further explore LYN-1604-induced autophagic mechanisms, some potential interactors, such as ATF3, RAD21, caspase3, performing comparative analysis. Intriguingly, induced death involved accompanied apoptosis. Moreover, good therapeutic effects on TNBC targeting vivo; thus making agonist novel small-molecule drug future