Cancer cells can be highly dependent on protein homeostasis pathways for their growth and survival. Here, Anderson et al. identify a potent and selective small-molecule inhibitor of p97 — a member of the AAA family of adenosine triphosphatases and a key regulator of protein homeostasis — named CB-5083. In cancer cells, CB-5083 blocked major protein-degradation functions, activating the unfolded protein response and apoptosis. CB-5083 significantly inhibited tumour growth in mouse haematological and solid tumour xenograft models and is currently in Phase I clinical trials.
References
Anderson D. J. et al. Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer Cell 28, 653–665 (2015)
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Crunkhorn, S. Disrupting protein homeostasis. Nat Rev Drug Discov 15, 18 (2016). https://doi.org/10.1038/nrd.2015.28
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DOI: https://doi.org/10.1038/nrd.2015.28