Developing FGFR4 inhibitors as potential anti-cancer agents via in silico design, supported by in vitro and cell-based testing

H. K. Ho, G. Németh, Y. R. Ng, E. Pang, C. Szántai-Kis, L. Zsákai, N. Breza, Z. Greff, Z. Horváth, J. Pató, I. Szabadkai, B. Szokol, F. Baska, L. Őrfi, A. Ullrich, G. Kéri, B. T. Chua

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC50 of 0.04 μM). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2α (FRS2α). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design.

Original languageEnglish
Pages (from-to)1203-1217
Number of pages15
JournalCurrent Medicinal Chemistry
Volume20
Issue number10
DOIs
Publication statusPublished - Apr 2013

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Receptor, Fibroblast Growth Factor, Type 4
Computer Simulation
Testing
Assays
Neoplasms
Phosphotransferases
Caspase 7
Phosphorylation
In Vitro Techniques
Drug Design
Scaffolds
Caspase 3
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Inhibitory Concentration 50
Proteins
Cells
Breast Neoplasms

Keywords

  • FGFR4
  • Inhibitor
  • Phosphorylation
  • Tyrosine Kinase

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Developing FGFR4 inhibitors as potential anti-cancer agents via in silico design, supported by in vitro and cell-based testing. / Ho, H. K.; Németh, G.; Ng, Y. R.; Pang, E.; Szántai-Kis, C.; Zsákai, L.; Breza, N.; Greff, Z.; Horváth, Z.; Pató, J.; Szabadkai, I.; Szokol, B.; Baska, F.; Őrfi, L.; Ullrich, A.; Kéri, G.; Chua, B. T.

In: Current Medicinal Chemistry, Vol. 20, No. 10, 04.2013, p. 1203-1217.

Research output: Contribution to journalArticle

Ho, HK, Németh, G, Ng, YR, Pang, E, Szántai-Kis, C, Zsákai, L, Breza, N, Greff, Z, Horváth, Z, Pató, J, Szabadkai, I, Szokol, B, Baska, F, Őrfi, L, Ullrich, A, Kéri, G & Chua, BT 2013, 'Developing FGFR4 inhibitors as potential anti-cancer agents via in silico design, supported by in vitro and cell-based testing', Current Medicinal Chemistry, vol. 20, no. 10, pp. 1203-1217. https://doi.org/10.2174/0929867311320100001
Ho, H. K. ; Németh, G. ; Ng, Y. R. ; Pang, E. ; Szántai-Kis, C. ; Zsákai, L. ; Breza, N. ; Greff, Z. ; Horváth, Z. ; Pató, J. ; Szabadkai, I. ; Szokol, B. ; Baska, F. ; Őrfi, L. ; Ullrich, A. ; Kéri, G. ; Chua, B. T. / Developing FGFR4 inhibitors as potential anti-cancer agents via in silico design, supported by in vitro and cell-based testing. In: Current Medicinal Chemistry. 2013 ; Vol. 20, No. 10. pp. 1203-1217.
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