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 Francia, Rick Betori, Karl Scheidt and Raymond Bergan ()
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Li Xu: Northwestern University
Ryan Gordon: Oregon Health & Science University
Rebecca Farmer: Northwestern University
Abhinandan Pattanayak: Oregon Health & Science University
Andrew Binkowski: University of Chicago
Xiaoke Huang: Northwestern University
Michael Avram: Northwestern University
Sankar Krishna: Northwestern University
Eric Voll: Northwestern University
Janet Pavese: Northwestern University
Juan Chavez: University of Washington
James Bruce: University of Washington
Andrew Mazar: Northwestern University
Antoinette Nibbs: Northwestern University
Wayne Anderson: Northwestern University
Lin Li: Northwestern University
Borko Jovanovic: Northwestern University
Sean Pruell: Northwestern University
Matias Valsecchi: Northwestern University
Giulio Francia: University of Texas at El Paso
Rick Betori: Northwestern University
Karl Scheidt: Northwestern University
Raymond Bergan: Oregon Health & Science University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04465-5

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DOI: 10.1038/s41467-018-04465-5

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