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

in European journal of medicinal chemistry by Yue Xu, Hang Yang, Yunxuan Li, Yuying Qi, Fangling Zhao, Yun Hong, Binbin Cheng, Zebei Lu, Jiaming Zhang, Chunyi Guo, Jie Fu, Qinrong Lin, Chunhong Chen, Ningning Shi, Jianping Cai, Ke Li, Shuanghu Wang, Ruijuan Gao, Dapeng Dai

TLDR

  • The study identified a new compound, DP-15, that targets specific proteins to kill cancer cells and showed promise in treating blood cancers
  • DP-15 demonstrated superior antiproliferative activity in vitro and in vivo compared to the initial compound

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.

Overview

  • The study focuses on translational readthrough (TR) regulation as a therapeutic strategy for cancer treatment, particularly in acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL)
  • The authors utilized a constructed monoclonal cell line AG-9 to screen compounds that induce TR and identified a BRD4-targeted PROTAC molecule, dBET57, which promotes TR by degrading GSPT1
  • The primary objective of the study is to develop and optimize TR-inducing compounds for the treatment of hematological malignancies

Comparative Analysis & Findings

  • dBET57 demonstrated significant antiproliferative activity against AML and NHL cells across a diverse panel of tumor cell lines, whereas optimized degraders showed superior antiproliferative activity in vitro and in vivo
  • Among optimized degraders, DP-15 emerged as a promising candidate, exhibiting significant anticancer activity against both AML and NHL cells while maintaining acceptable safety profiles for normal leukocytes
  • DP-15 demonstrated enhanced antitumor efficacy in mouse CDX models compared to dBET57

Implications and Future Directions

  • The study highlights the potential of dual BRD4 and GSPT1 degraders, such as DP-15, as effective therapeutic agents for the treatment of hematological malignancies
  • Future studies could explore the mechanism of action and toxicity profiles of DP-15 and its analogs to optimize their efficacy and safety for clinical use
  • The findings of this study may lead to the development of novel therapeutic strategies for the treatment of AML and NHL, as well as other hematological malignancies
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