Reference Detail

Ref Type

Journal Article

PMID

(23804704)

Authors

Burbridge MF, Bossard CJ, Saunier C, Fejes I, Bruno A, Léonce S, Ferry G, Da Violante G, Bouzom F, Cattan V, Jacquet-Bescond A, Comoglio PM, Lockhart BP, Boutin JA, Cordi A, Ortuno JC, Pierré A, Hickman JA, Cruzalegui FH, Depil S

Title

S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	12	9	2013 Sep	1749-62	Mol Cancer Ther

URL

Abstract Text

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749-62. ©2013 AACR.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
S-49076	S-49076	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
S-49076		S49076	Aurkb Inhibitors 21 AXL Inhibitor 30 FGFR1 Inhibitor 28 FGFR2 Inhibitor 23 FGFR3 Inhibitor 19 MET Inhibitor 59	S-49076 is a multi-kinase inhibitor that inhibits wild-type and mutant forms of MET and FGFR1-2, as well as FGFR3, AXL, MER, and AURKB, resulting in decreased downstream signaling, and potentially resulting in decreased tumor growth (PMID: 23804704, PMID: 28624695, PMID: 28619752).

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
FGFR2 act mut	stomach carcinoma	sensitive	S-49076	Preclinical - Cell line xenograft	Actionable	In a preclinical study, S-49076 inhibited Met activation, resulting in growth inhibition of gastric carcinoma cells harboring FGFR2 activating mutations in culture and in cell line xenograft models (PMID: 23804704).	23804704
FGFR3 act mut	urinary bladder cancer	predicted - sensitive	S-49076	Preclinical	Actionable	In a preclinical study, S-49076 inhibited autophosphorylation of FGFR3 and downstream signaling in bladder cancer cells over expressing constitutively active FGFR3 in culture (PMID: 23804704).	23804704