Anti-tumor effects of an ID antagonist with no observed acquired resistance

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 neova...

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Published in:NPJ breast cancer 2021-05, Vol.7 (1), p.58-58, Article 58
Main Authors: Wojnarowicz, Paulina M., Escolano, Marta Garcia, Huang, Yun-Han, Desai, Bina, Chin, Yvette, Shah, Riddhi, Xu, Sijia, Yadav, Saurabh, Yaklichkin, Sergey, Ouerfelli, Ouathek, Soni, Rajesh Kumar, Philip, John, Montrose, David C., Healey, John H., Rajasekhar, Vinagolu K., Garland, William A., Ratiu, Jeremy, Zhuang, Yuan, Norton, Larry, Rosen, Neal, Hendrickson, Ronald C., Zhou, Xi Kathy, Iavarone, Antonio, Massague, Joan, Dannenberg, Andrew J., Lasorella, Anna, Benezra, Robert
Format: Article
Language:English
Subjects:
631/67/1059
631/67/322
Biomedical and Life Sciences
Biomedicine
Breast cancer
Cancer Research
Cell Biology
Genetics
Health care policy
Human Genetics
Medical research
Metastasis
Oncology
Pathology
Proteins
Reactive oxygen species
Transcription factors
Tumors
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Summary: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.
ISSN:2374-4677
2374-4677
DOI:10.1038/s41523-021-00266-0