TY - JOUR
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 - 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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U2 - 10.1038/s41467-018-04465-5
DO - 10.1038/s41467-018-04465-5
M3 - Article
C2 - 29934502
AN - SCOPUS:85048955241
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2454
ER -