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New class of cancer suppressing chemical identified

23 April 2013. A multinational consortium of scientists have identified and characterized an entirely novel kind of allosteric inhibitor of fibroblast growth factor (FGF) receptor signaling that inhibits tumor angiogenesis and growth. Receptor tyrosine kinases (RTK) are of major importance as key targets for anticancer drug development. Classic examples of RTK blockers include antibodies inhibiting orthosteric ligand binding, but small molecules that bind the extracellular domain of RTKs have traditionally not been considered because they are thought to be too small to competitevely block binding of the much larger polypeptideligands. In a recent publication in the journal Cancer Cell, the scientists identified a small-molecule chemical compound, SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling through allosteric mechanisms after binding to the extracellular FGFR domain (Bono et al. 2013). Oral delivery of SSR inhibits tumor growth and amplifies anti-angiogenic drug therapy.

The molecular mechanism of SSR as an extracellularly acting allosteric inhibitor of FGF receptor signaling was established through crystallography studies, nuclear magnetic resonance and Fourier transform infrared spectroscopy as well as molecular dynamics simulations, free energy calculations, structure-activity relationship analysis and FGFR mutagenesis, as described in a second publication in Cancer Cell (Herbert et al., 2013).

These findings offer strong incentives to develop orally-active small-molecule RTK inhibitors with allosteric properties and opportunities for improved anticancer treatment.


Prof. Dr. Harald Schwalbe
Institut für Organische Chemie und Chemische Biologie Goethe-Universität Frankfurt
Max-von-Laue-Str. 7
60438 Frankfurt am Main
Telefon:    +49 (0)69 798-29737    
Fax:    +49 (0)69 798-29515    
Email: schwalbe@nmr.uni-frankfurt.de


Full references
Bono F, De Smet F, Herbert C, De Bock K, Georgiadou M, Fons P, Tjwa M, Alcouffe C, Ny A, Bianciotto M, Jonckx B, Murakami M, Lanahan A A, Michielsen C, Sibrac D, Dol-Gleizes F, Mazzone M, Zacchigna S, Herault J P, Fischer C, Rigon P, Ruiz de Almodovar C, Claes F, Blanc I, Poesen K, Zhang J, Segura I, Gueguen G, Bordes M F, Lambrechts D, Broussy R, van de Wouwer M, Michaux C, Shimada T, Jean I, Blacher S, Noel A, Motte P, Rom E, Rakic J M, Katsuma S, Schaeffer P, Yayon A, Van Schepdael A, Schwalbe H, Gervasio F L, Carmeliet G, Rozensky J, Dewerchin M, Simons M, Christopoulos A, Herbert J M, Carmeliet P (2013) Inhibition of Tumor Angiogenesis and Growth by a Small-Molecule Multi-FGF Receptor Blocker with Allosteric Properties. Cancer Cell 23: 477–488 More ...

Herbert C, Schieborr U, Saxena K, Juraszek J, De Smet F, Alcouffe C, Bianciotto M, Saladino G, Sibrac D, Kudlinzki D, Sreeramulu S, Brown A, Rigon P, Herault J P, Lassalle G, Blundell T L, Rousseau F, Gils A, Schymkowitz J, Tompa P, Herbert J M, Carmeliet P, Gervasio F L, Schwalbe H, Bono F (2013) Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling. Cancer Cell 23: 489-501. More ...