Small-molecule-induced liquid-liquid phase separation suppresses the carcinogenesis of β-catenin

Biomolecular condensates are droplet-like membrane-less compartments in cells that can sequester proteins. Modulating these condensates offers a promising way to durably inhibit disease-driving proteins that lack enzymatic activity and thus elude traditional drug targeting. However, many such proteins remain beyond the reach of current condensate-modulating strategies. Here we show an alternative approach: by destabilizing target proteins, we directly induce their liquid-liquid phase separation (LLPS), causing them to form condensates. Using this strategy, we develop a small molecule RQ that forces β-catenin (an oncogenic protein in liver cancer) into cytoplasmic condensates. This sequestration prevents…

• NN
  National Natural Science Foundation of China

  Awards: 82272782, No. 22007076, 32171256
• RP
  Recruitment Program of Global Experts
• NK
  National Key Research and Development Program of China

  Award: 2022YFE0133500