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Bioorg Med Chem Lett. 2017 Sep 1;27(17):3992-4000. doi: 10.1016/j.bmcl.2017.07.063. Epub 2017 Jul 25.

Pyridine-pyrimidine amides that prevent HGF-induced epithelial scattering by two distinct mechanisms.

Author information

1
Frost Biologic, Inc., 5201 South Green St., Suite 160, Salt Lake City, UT 84123, USA.
2
Department of Physiology and Developmental Biology, Brigham Young University, 4005 LSB, Provo, UT 84602, USA.
3
Structure-ase, Inc., Saratoga Springs, UT 84045, USA.
4
TA Instruments, Lindon, UT 84020, USA.
5
Frost Biologic, Inc., 5201 South Green St., Suite 160, Salt Lake City, UT 84123, USA; Department of Physiology and Developmental Biology, Brigham Young University, 4005 LSB, Provo, UT 84602, USA. Electronic address: marchansen@byu.edu.

Abstract

Stimulation of cultured epithelial cells with scatter factor/hepatocyte growth factor (HGF) results in individual cells detaching and assuming a migratory and invasive phenotype. Epithelial scattering recapitulates cancer progression and studies have implicated HGF signaling as a driver of cancer metastasis. Inhibitors of HGF signaling have been proposed to act as anti-cancer agents. We previously screened a small molecule library for compounds that block HGF-induced epithelial scattering. Most hits identified in this screen exhibit anti-mitotic properties. Here we assess the biological mechanism of a compound that blocks HGF-induced scattering with limited anti-mitotic activity. Analogs of this compound have one of two distinct activities: inhibiting either cell migration or cell proliferation with cell cycle arrest in G2/M. Each activity bears unique structure-activity relationships. The mechanism of action of anti-mitotic compounds is by inhibition of microtubule polymerization; these compounds entropically and enthalpically bind tubulin in the colchicine binding site, generating a conformational change in the tubulin dimer.

KEYWORDS:

Cancer; Cell migration; Epithelial-mesenchymal transition (EMT); Microtubule

PMID:
28780159
DOI:
10.1016/j.bmcl.2017.07.063
[Indexed for MEDLINE]

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