期刊
NPJ BREAST CANCER
卷 7, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41523-021-00266-0
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资金
- Sloan Kettering Institute
- NIH [P30 CA008748]
- NCI [PO1 CA094060]
- Breast Cancer Research Foundation
- Botwinick-Wolfensohn foundation
- NCI/NIH [1R43CA150448 01]
- National Institute of Health [R01CA101644, R01CA131126]
- Fonds de recherche du Quebec - Sante (FRQS)
- Valencian Government of Spain (GVA)
- European Social Fund [ACIF/2018/004, BEFPI/2018/029]
AGX51 targets ID proteins in cancer cells, inhibiting cell growth and enhancing ROS production, showing potential therapeutic effects for multiple cancers.
ID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impairs cell growth and viability that results from an increase in reactive oxygen species (ROS) production upon ID degradation. In mouse models, AGX51 treatment suppresses breast cancer colonization in the lung, regresses the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduces tumor burden in sporadic colorectal neoplasia. Furthermore, in cells and mice, we fail to observe acquired resistance to AGX51 likely the result of the inability to mutate the binding pocket without loss of ID function and efficient degradation of the ID proteins. Thus, AGX51 is a first-in-class compound that antagonizes ID proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.
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