Pyridine-pyrimidine amides that prevent HGF-induced epithelial scattering by two distinct mechanisms
- Resource Type
- Authors
- Taylor H. Hoj; Marc D.H. Hansen; Colette Quinn; Collin A. Ritchie; Carter J. Payne; Steven R. Herron; Adam Siddiqui-Jain; Jeffrey T. Schuler; Jacob P. Hoj; J. Blade Hargiss
- Source
- Bioorganicmedicinal chemistry letters. 27(17)
- Subject
- 0301 basic medicine
Pyridines
Clinical Biochemistry
Pharmaceutical Science
Antineoplastic Agents
Biochemistry
Microtubule polymerization
03 medical and health sciences
Structure-Activity Relationship
0302 clinical medicine
Microtubule
Cell Movement
Cell Line, Tumor
Drug Discovery
medicine
Humans
Molecular Biology
Cell Proliferation
biology
Dose-Response Relationship, Drug
Molecular Structure
Chemistry
Cell growth
Hepatocyte Growth Factor
Organic Chemistry
Cell migration
Epithelial Cells
Small molecule
Amides
Cell biology
030104 developmental biology
Tubulin
Pyrimidines
Mechanism of action
030220 oncology & carcinogenesis
biology.protein
MCF-7 Cells
Molecular Medicine
Hepatocyte growth factor
medicine.symptom
Drug Screening Assays, Antitumor
medicine.drug
- Language
- ISSN
- 1464-3405
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.