Dissecting Programmed Cell Death with Small Molecules

• DOI: 10.1021/acs.accounts.9b00600
• Publication Date: 2020-04-16T14:15:55Z
• Authors: Yingjie Bai; Hiu C. Lam; Xiaoguang Lei
• Keywords: Chemical Biology; Natural product; RIPK1

ConspectusProgrammed cell death (PCD) is fundamentally an indispensable process in all cellular activities, including development, wound healing, and immune surveillance of tumors (Galluzzi, L. et al. Cell Death Differ. 2018, 25, 486−541). Malfunctioning PCD has been shown to be closely related human diseases such as acute pancreatitis, neurodegenerative diseases, diverse types cancers. To date, multiple processes have discovered the corresponding regulatory pathways elucidated. For example, apoptosis autophagy are two mechanisms that well studied by sophisticated models probe toolkits. However, limited genetic chemical tools for other hamper elucidation their molecular mechanisms. Our group studying using both function-oriented synthesis biology strategies, development probes based on novel modulators. instance, downstream programmed necrosis (or necroptosis) inhibitor necrosulfonamide, we used a unveil functional protein was not previously implicated necroptosis, mixed lineage kinase domain-like (MLKL). In addition, high throughput screening medicinal chemistry enabled discovery bioymifi, small molecule agonist which selectively causes oligomerization receptor 5 (DR5), induce extrinsic apoptosis. Furthermore, developed biomimetic synthetic strategy Diels–Alder reactions total syntheses ainsliadimers A B, ainsliatrimers gonchnatiolides A–C, natural product inhibitors or activators PCD. Using ainsliadimer probe, elucidated inhibits NF-κB pathway covalently binding Cys46 IKKβ triggers cancer cells. We also revealed allosterically inhibited A. addition synthesis, bioorthogonal click hetero-Diels–Alder cycloaddition vinyl thioether o-quinolinone quinone methide (TQ-ligation) facilitate target identification. The combination TQ-ligation enables subcellular imaging identification ainsliatrimer PPARγ. applied heat shock 90 (HSP90) one proteins kongensin confirmed attaches Cys420 within HSP90 demonstrated blocks interaction between CDC37 subsequently necroptosis. these modulators provides only effective fundamental biomedical research, but foundation drug targeting important cancers inflammation caused malfunction