Development of a molecular glue-based Lin28 degrader to regulate cellular proliferation and stemness

Let-7 microRNAs (miRNAs) regulate cellular processes including stemness and proliferation. Lin28, an RNA-binding protein, controls let-7 miRNA biogenesis and is a key factor in maintaining stem cell properties. We developed SB1349, a novel molecular glue-based degrader targeting Lin28. SB1349 induces Lin28 degradation through a proteasome-dependent pathway, enhances let-7 miRNA levels, and downregulates oncogenes c-Myc and IMP1. SB1349 also promotes the differentiation in neuroblastoma cells, highlighting its potential as a therapeutic agent for various diseases. A molecular glue-based Lin28 degrader SB1349 showed dose-dependent Lin28A/B degradation, let-7 miRNA upregulation, and oncogene downregulation. SB1349 also promoted differentiation in SH-SY5Y cells, highlighting its therapeutic potential.