Discovery of highly potent dual GSPT1/BRD4 degraders with anti-AML activity

Translational readthrough (TR) regulation has emerged as a promising therapeutic strategy for cancer treatment. Utilizing a constructed monoclonal cell line AG-9, designed for screening compounds that induce TR, we identified a BRD4-targeted PROTAC molecule, dBET57, that promotes TR by degrading GSPT1. Notably, dBET57 exhibited significant antiproliferative activity against acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) cells across a diverse panel of tumor cell lines. Building on these findings, we optimized the structure of dBET57, leading to the development of analogs with enhanced dual-target degradation capabilities. Most of these optimized degraders demonstrated superior antiproliferative activity in vitro against various AML and NHL cell lines when compared to dBET57. Among them, DP-15 emerged as a particularly promising candidate, exhibiting significant anticancer activity against both AML and NHL cells while maintaining acceptable safety profiles for normal leukocytes. Furthermore, DP-15 demonstrated enhanced antitumor efficacy in mouse cell-derived xenograft (CDX) models. Our findings highlight the potential of dual BRD4 and GSPT1 degraders, such as DP-15, as effective therapeutic agents for the treatment of hematological malignancies.