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

• Published in: Bioorganic & medicinal chemistry letters 2017-09, Vol.27 (17), p.3992-4000
• Main Authors: Siddiqui-Jain, Adam, Hoj, Jacob P., Hargiss, J. Blade, Hoj, Taylor H., Payne, Carter J., Ritchie, Collin A., Herron, Steven R., Quinn, Colette, Schuler, Jeffrey T., Hansen, Marc D.H.
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial-mesenchymal transition (EMT); Hepatocyte Growth Factor - antagonists & inhibitors; Hepatocyte Growth Factor - metabolism; Humans; MCF-7 Cells; Microtubule; Molecular Structure; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.07.063

[Display omitted] 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.