Year: 2018
Type: article
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.
Source: Nature Communications
Authors: 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
Language: English
Topic: Heat shock proteins research
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G102163711, G107546177, G1313983767, G1581679921, G1664757510, G2287611682, G262962599, G3075337988, Quantitation of protein interactions in cancer cells, G4030212589, G498139845, SPORE in Prostate Cancer, G5197886545, Midwest Center for Structural Genomics, G5607048534, G6848031779, G6918803902, Chemistry of Life Processes Predoctoral Training Program, G7822115964, G8090146412, G9000019905, G9000044262, G9000062923, G9000156400, G9000181008, G969889393, G993149817
OpenAlex ID: W2809026310