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; Raymond Bergan

doi:10.1038/s41467-018-04465-5

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

Knight Cancer Institute

Research output: Contribution to journal › Article › peer-review

24 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 language	English (US)
Article number	2454
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04465-5
State	Published - Dec 1 2018

ASJC Scopus subject areas

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

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10.1038/s41467-018-04465-5

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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), Article 2454. https://doi.org/10.1038/s41467-018-04465-5

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, Francia, G, Betori, R, Scheidt, K & Bergan, R 2018, 'Precision therapeutic targeting of human cancer cell motility', Nature communications, vol. 9, no. 1, 2454. https://doi.org/10.1038/s41467-018-04465-5

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title = "Precision therapeutic targeting of human cancer cell motility",

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.",

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

note = "Funding Information: Financial support for this research was provided to R.Ber. by the Veterans Administration (IBX002842A) and the National Institutes of Health (R01 CA122985, Prostate SPORE CA90386 and P30 CA069533), to J.B. by the National Institutes of Health (R01 GM086688) and to A.B. from the National Institutes of Health (GM094585), resources of the Argonne Leadership Computing Facility at Argonne National Laboratory (supported by the Office of Science of the US Department of Energy under contract DE-AC02- 06CH11357) and allocations for computing (supported by the Department of Energy's Innovative and Novel Computational Impact on Theory and Experiment (INCITE) program). We wish to thank I. Ogden for technical support in performing cell and molecular-based assays, M. Lin for help in performing luciferase assays, A. Yemelyanov for help in transfection, and Mikko Taipale and Susan Lindquist for generously providing LUMIER reagents Funding Information: Financial support for this research was provided to R.Ber. by the Veterans Administration (IBX002842A) and the National Institutes of Health (R01 CA122985, Prostate SPORE CA90386 and P30 CA069533), to J.B. by the National Institutes of Health (R01 GM086688) and to A.B. from the National Institutes of Health (GM094585), resources of the Argonne Leadership Computing Facility at Argonne National Laboratory (supported by the Office of Science of the US Department of Energy under contract DE-AC02-06CH11357) and allocations for computing (supported by the Department of Energy{\textquoteright}s Innovative and Novel Computational Impact on Theory and Experiment (INCITE) program). We wish to thank I. Ogden for technical support in performing cell and molecular-based assays, M. Lin for help in performing luciferase assays, A. Yemelyanov for help in transfection, and Mikko Taipale and Susan Lindquist for generously providing LUMIER reagents. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

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doi = "10.1038/s41467-018-04465-5",

language = "English (US)",

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T1 - Precision therapeutic targeting of human cancer cell motility

AU - Xu, Li

AU - Gordon, Ryan

AU - Farmer, Rebecca

AU - Pattanayak, Abhinandan

AU - Binkowski, Andrew

AU - Huang, Xiaoke

AU - Avram, Michael

AU - Krishna, Sankar

AU - Voll, Eric

AU - Pavese, Janet

AU - Chavez, Juan

AU - Bruce, James

AU - Mazar, Andrew

AU - Nibbs, Antoinette

AU - Anderson, Wayne

AU - Li, Lin

AU - Jovanovic, Borko

AU - Pruell, Sean

AU - Valsecchi, Matias

AU - Francia, Giulio

AU - Betori, Rick

AU - Scheidt, Karl

AU - Bergan, Raymond

N1 - Funding Information: Financial support for this research was provided to R.Ber. by the Veterans Administration (IBX002842A) and the National Institutes of Health (R01 CA122985, Prostate SPORE CA90386 and P30 CA069533), to J.B. by the National Institutes of Health (R01 GM086688) and to A.B. from the National Institutes of Health (GM094585), resources of the Argonne Leadership Computing Facility at Argonne National Laboratory (supported by the Office of Science of the US Department of Energy under contract DE-AC02- 06CH11357) and allocations for computing (supported by the Department of Energy's Innovative and Novel Computational Impact on Theory and Experiment (INCITE) program). We wish to thank I. Ogden for technical support in performing cell and molecular-based assays, M. Lin for help in performing luciferase assays, A. Yemelyanov for help in transfection, and Mikko Taipale and Susan Lindquist for generously providing LUMIER reagents Funding Information: Financial support for this research was provided to R.Ber. by the Veterans Administration (IBX002842A) and the National Institutes of Health (R01 CA122985, Prostate SPORE CA90386 and P30 CA069533), to J.B. by the National Institutes of Health (R01 GM086688) and to A.B. from the National Institutes of Health (GM094585), resources of the Argonne Leadership Computing Facility at Argonne National Laboratory (supported by the Office of Science of the US Department of Energy under contract DE-AC02-06CH11357) and allocations for computing (supported by the Department of Energy’s Innovative and Novel Computational Impact on Theory and Experiment (INCITE) program). We wish to thank I. Ogden for technical support in performing cell and molecular-based assays, M. Lin for help in performing luciferase assays, A. Yemelyanov for help in transfection, and Mikko Taipale and Susan Lindquist for generously providing LUMIER reagents. Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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VL - 9

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JF - Nature communications

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ER -

Precision therapeutic targeting of human cancer cell motility

Abstract

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