2. Academic Validation
  3. Precision therapeutic targeting of human cancer cell motility

Precision therapeutic targeting of human cancer cell motility

  • Nat Commun. 2018 Jun 22;9(1):2454. doi: 10.1038/s41467-018-04465-5.
Li Xu 1 2,  Ryan Gordon 3,  Rebecca Farmer 4,  Abhinandan Pattanayak 3,  Andrew Binkowski 5,  Xiaoke Huang 1,  Michael Avram 6,  Sankar Krishna 1,  Eric Voll 1,  Janet Pavese 1,  Juan Chavez 7,  James Bruce 7,  Andrew Mazar 4,  Antoinette Nibbs 4,  Wayne Anderson 8,  Lin Li 9,  Borko Jovanovic 10,  Sean Pruell 1,  Matias Valsecchi 1,  Giulio Francia 11,  Rick Betori 4,  Karl Scheidt 4,  Raymond Bergan 12
Affiliations

Affiliations

  • 1 Department of Medicine, Northwestern University, Chicago, IL, 60611, USA.
  • 2 Department of Gastroenterology, Xiang'an Hospital of Xiamen University, Fujian, 361101, Xiamen, China.
  • 3 Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA.
  • 4 Department of Chemistry, Northwestern University, Evanston, IL, 60208, USA.
  • 5 Department of Computer Science, University of Chicago, Chicago, IL, 60637, USA.
  • 6 Department of Anesthesiology, Northwestern University, Chicago, IL, 60611, USA.
  • 7 Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA.
  • 8 Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, IL, 60611, USA.
  • 9 Department of Pathology, Northwestern University, Chicago, IL, 60611, USA.
  • 10 Department of Preventive Medicine, Northwestern University, Chicago, IL, 60611, USA.
  • 11 Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, 79968, USA.
  • 12 Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA. bergan@ohsu.edu.
PMID: 29934502 DOI: 10.1038/s41467-018-04465-5
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-120548
    99.52%, 细胞运动/侵袭抑制剂
    HSP
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