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


Authors: Wojnarowicz, P. M.; Garcia Escolano, M.; Huang, Y. H.; Desai, B.; Chin, Y.; Shah, R.; Xu, S.; Yadav, S.; Yaklichkin, S.; Ouerfelli, O.; Soni, R. K.; Philip, J.; Montrose, D. C.; Healey, J. H.; Rajasekhar, V. K.; Garland, W. A.; Ratiu, J.; Zhuang, Y.; Norton, L.; Rosen, N.; Hendrickson, R. C.; Zhou, X. K.; Iavarone, A.; Massague, J.; Dannenberg, A. J.; Lasorella, A.; Benezra, R.
Article Title: Anti-tumor effects of an ID antagonist with no observed acquired resistance
Abstract: 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. © 2021, The Author(s).
Journal Title: npj Breast Cancer
Volume: 7
ISSN: 2374-4677
Publisher: Nature Publishing Group  
Date Published: 2021-05-24
Start Page: 58
Language: English
DOI: 10.1038/s41523-021-00266-0
PROVIDER: scopus
PUBMED: 34031428
PMCID: PMC8144414
DOI/URL:
Notes: Article -- Export Date: 1 July 2021 -- Source: Scopus
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