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	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	23	4	2013 Apr 15	477-88	Cancer Cell

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
SSR128129E	SSR128129E	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
SSR128129E			FGFR Inhibitor (Pan) 26	SSR128129E is an allosteric pan-FGFR inhibitor which may inhibit angiogenesis and tumor growth (PMID: 23597562, PMID: 24760775, PMID: 29656465, PMID: 27479031).

Gene	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
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