Precision therapeutic targeting of human cancer cell motility

Li Xu, Ryan Gordon, Rebecca Farmer, Abhinandan Pattanayak, Andrew Binkowski, Xiaoke Huang, Michael Avram, Sankar Krishna, Eric Voll, Janet Pavese, Juan Chavez, James Bruce, Andrew Mazar, Antoinette Nibbs, Wayne Anderson, Lin Li, Borko Jovanovic, Sean Pruell, Matias Valsecchi, Giulio FranciaRick Betori, Karl Scheidt, Raymond Bergan

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Increased cancer cell motility constitutes a root cause of end organ destruction and mortality, but its complex regulation represents a barrier to precision targeting. We use the unique characteristics of small molecules to probe and selectively modulate cell motility. By coupling efficient chemical synthesis routes to multiple upfront in parallel phenotypic screens, we identify that KBU2046 inhibits cell motility and cell invasion in vitro. Across three different murine models of human prostate and breast cancer, KBU2046 inhibits metastasis, decreases bone destruction, and prolongs survival at nanomolar blood concentrations after oral administration. Comprehensive molecular, cellular and systemic-level assays all support a high level of selectivity. KBU2046 binds chaperone heterocomplexes, selectively alters binding of client proteins that regulate motility, and lacks all the hallmarks of classical chaperone inhibitors, including toxicity. We identify a unique cell motility regulatory mechanism and synthesize a targeted therapeutic, providing a platform to pursue studies in humans.

Original languageEnglish (US)
Article number2454
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Xu, L., Gordon, R., Farmer, R., Pattanayak, A., Binkowski, A., Huang, X., Avram, M., Krishna, S., Voll, E., Pavese, J., Chavez, J., Bruce, J., Mazar, A., Nibbs, A., Anderson, W., Li, L., Jovanovic, B., Pruell, S., Valsecchi, M., ... Bergan, R. (2018). Precision therapeutic targeting of human cancer cell motility. Nature communications, 9(1), [2454]. https://doi.org/10.1038/s41467-018-04465-5