ODM-203 是 FGFR 和 VEGFR 家族的抑制剂，具有显著的抗肿瘤活性，能够诱导抗肿瘤免疫。

ODM-203, a Selective Inhibitor of FGFR and VEGFR, Shows Strong Antitumor Activity, and Induces Antitumor Immunity

ODM-203 inhibits FGFR and VEGFR family kinases selectively and with equal potency in the low nanomolar range (IC50 6-35 nmol/L) in biochemical assays.?In cellular assays, ODM-203 inhibits VEGFR-induced tube formation (IC50 33 nmol/L) with similar potency as it inhibits proliferation in FGFR-dependent cell lines (IC50 50-150 nmol/L).

In vivo, ODM-203 shows strong antitumor activity in both FGFR-dependent xenograft models and in an angiogenic xenograft model at similar well-tolerated doses.

Inhibition of FRS2 Tyrosine 196 phosphorylation by ODM-203 in FGFR-dependent cell lines was measured using an MSD 96-well multiarray Phospho-FRS2 Tyr196 assay (MesoScale Diagnostics) .?Briefly, the cell lines were seeded at a density of 75,000 cells/well on poly-d-lysine-coated 96-well plates?in the cell culture media .?The cells were allowed to attach overnight and subsequently treated with the vehicle (0.5% DMSO) or increasing concentrations of ODM-203 for 20 minutes.?The cell culture media were aspirated and the cells lysed in MSD Tris Lysis Buffer?supplemented with 10 mmol/L NaF, 1× phosphatase inhibitor cocktail 2 and 3 and Complete Protease Inhibitor Cocktail .?The electrochemiluminescence signal was detected with a SECTOR Imager 2400 plate reader coupled to a CCD camera.?Data were expressed as percentages of vehicle control values and analyzed with GrapPadPrism 7.03 .?Each test concentration was studied at least in triplicate and inhibition percentages were calculated for the parallel samples.?Average IC50 values were calculated from two independent experiments.

Athymic Nude-Foxn1nu female mice (9 weeks old;?Harlan, the Netherlands) were subcutaneously injected with 1 million H1581, KMS11, RT4, or SNU16 cells in 100 μL of McCoy's 5a modified medium and Matrigel (BD) (1:1).?Tumor growth was monitored twice weekly by caliper measurements.?Oral treatment with ODM-203 and AZD-4547 was started when the average tumor volume reached 100 mm^3 and continued for 21 days for the RT4 xenograft model (n = 12/group) and 12 days for the SNU16 xenograft model (n = 6/group).?Necropsy, and plasma and tumor sampling were carried out 4 hours after the last dosing.Doses for 12.5 mg/kg AZD4547 and 40 mg/kg sorafenib were chosen based on published data.?Oral treatment (ODM-203 or AZD4547) was initiated when the average tumor volume reached ≈125 mm^3.?Mean tumor volumes were calculated for each treatment group.

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C26H21F2N5O2S

505.54

DMSO:10 mM
Powder: -20°C for 3 years
In solvent: -80°C for 2 years