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Discovery of highly potent dual GSPT1/BRD4 degraders with anti-AML activity
Yue Xu1, Hang Yang1, Yunxuan Li2
1The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital /National Center of Gerontology of National Health Commission, Beijing, 100730, PR China.
Abstract:
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.
Insights
Researchers developed novel dual degraders targeting BRD4 and GSPT1 for cancer therapy. The compound DP-15 shows significant promise in treating acute myeloid leukemia and non-Hodgkin lymphoma, with enhanced efficacy and safety.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Translational readthrough (TR) is a key regulatory mechanism with therapeutic potential in cancer.
- Targeting BRD4 and GSPT1 offers a novel strategy for cancer treatment.
- Existing therapies for hematological malignancies have limitations, necessitating new approaches.
Purpose of the Study:
- To identify compounds that induce translational readthrough (TR) for cancer therapy.
- To develop and evaluate novel dual BRD4 and GSPT1 degraders.
- To assess the therapeutic potential of these degraders in hematological malignancies.
Main Methods:
- Utilized a monoclonal cell line (AG-9) for screening TR-inducing compounds.
- Identified and optimized PROTAC molecules, including dBET57 and its analogs.
- Evaluated antiproliferative activity against acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) cell lines in vitro.
- Assessed antitumor efficacy in cell-derived xenograft (CDX) mouse models.
Main Results:
- Identified dBET57, a BRD4-targeted PROTAC that degrades GSPT1 and shows antiproliferative activity in AML and NHL cells.
- Developed optimized analogs with enhanced dual-target degradation.
- DP-15, a lead analog, demonstrated superior in vitro antiproliferative activity and antitumor efficacy in CDX models.
- DP-15 exhibited an acceptable safety profile for normal leukocytes.
Conclusions:
- Dual BRD4 and GSPT1 degraders represent a promising therapeutic strategy for hematological malignancies.
- DP-15 is a potent anticancer agent with potential for treating AML and NHL.
- Further development of dual degraders could lead to effective treatments for blood cancers.
