Reference Detail

Ref Type Journal Article
PMID (23597562)
Authors 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 AA, Michielsen C, Sibrac D, Dol-Gleizes F, Mazzone M, Zacchigna S, Herault JP, Fischer C, Rigon P, Ruiz de Almodovar C, Claes F, Blanc I, Poesen K, Zhang J, Segura I, Gueguen G, Bordes MF, Lambrechts D, Broussy R, van de Wouwer M, Michaux C, Shimada T, Jean I, Blacher S, Noel A, Motte P, Rom E, Rakic JM, Katsuma S, Schaeffer P, Yayon A, Van Schepdael A, Schwalbe H, Gervasio FL, Carmeliet G, Rozensky J, Dewerchin M, Simons M, Christopoulos A, Herbert JM, Carmeliet P
Title Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties.
Journal Cancer cell
Vol 23
Issue 4
Date 2013 Apr 15
URL
Abstract Text Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
SSR128129E FGFR Inhibitor (Pan) 18 SSR128129E is an allosteric pan-FGFR inhibitor which may inhibit angiogenesis and tumor growth (PMID: 23597562, PMID: 24760775).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 wild-type myeloid neoplasm sensitive SSR128129E Preclinical Actionable In a preclinical study, SSR128129E inhibited proliferation of myeloma cells expressing wild-type FGFR3 in culture (PMID: 23597562). 23597562
Unknown unknown Advanced Solid Tumor not applicable SSR128129E Preclinical - Cell line xenograft Actionable In a preclinical study, SSR128129E inhibited tumor growth in several solid tumor cell line xenograft models (PMID: 23597562). 23597562
FGFR3 wild-type myeloid neoplasm sensitive SU5402 Preclinical - Cell culture Actionable In a preclinical study, SU5402 inhibited proliferation of myeloma cells expressing wild-type FGFR3 in culture (PMID: 23597562). 23597562
FGFR3 K650E myeloid neoplasm sensitive SU5402 Preclinical - Cell culture Actionable In a preclinical study, SU5402 inhibited proliferation of myeloma cells expressing FGFR3 K650E in culture (PMID: 23597562). 23597562
FGFR3 K650E myeloid neoplasm no benefit SSR128129E Preclinical Actionable In a preclinical study, SSR128129E did not inhibit proliferation of myeloma cells expressing FGFR3 K650E in culture (PMID: 23597562). 23597562