A pan-FGFR inhibitor
Erdafitinib (JNJ-42756493) is a potent and orally available FGFR family inhibitor; inhibits FGFR1/2/3/4 with IC50s of 1.2, 2.5, 3.0 and 5.7 nM, respectively.
Erdafitinib inhibits the tyrosine kinase activities of FGFR1-4 in time-resolved fluorescence assays with IC50 values of 1.2, 2.5, 3.0 and 5.7 nM, respectively. The closely related VEGFR2 kinase is less potently inhibited (30-fold less potent compared to FGFR1) by erdafitinib, with an IC50 value of 36.8 nM. JNJ-42756493 binds FGFR1, 3, 4, and 2 with Kd values of 0.24, 1.1, 1.4 and 2.2 nM, respectively. The Kd value for VEGFR2 is higher at 6.6 nM. JNJ-42756493 inhibits proliferation of FGFR1, 3, and 4 expressing cells with IC50 values of 22.1, 13.2, and 25nM, respectively[1].
In xenografts from human tumor cell lines or patient-derived tumor tissue with activating FGFR alterations, Erdafitinib administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors[1].
参考文献:
[1]. Perera TP, et al. Discovery and pharmacological characterization of JNJ-42756493 (erdafitinib), a functionally selective small molecule FGFR family inhibitor. Mol Cancer Ther. 2017 Mar 24. pii: molcanther.0589.2016.
|
Cell experiment: |
Erdafitinib is dissolved in DMSO. KATO III, RT-112, A-204, RT-4, DMS-114, A-427 and MDA-MB-453 cells are treated with erdafitinib (from 10 μM to 0.01 nM in 2% DMSO, final concentration). Following 4-day incubation, cell viability is determined using MTT reagent. The optical density is determined at 540 nm[1]. |
|
Animal experiment: |
Mice: Mice bearing SNU-16 human gastric carcinoma (FGFR2 amplified) xenograft tumors are dosed orally with 0, 3, 10 or 30mg/kg JNJ-42756493. Tumor tissue and mouse plasma (3 mice per time point) are harvested at 0.5, 1, 3, 7, 16 and 24h post-dosing[1]. |
|
参考文献: [1]. Perera TP, et al. Discovery and pharmacological characterization of JNJ-42756493 (erdafitinib), a functionally selective small molecule FGFR family inhibitor. Mol Cancer Ther. 2017 Mar 24. pii: molcanther.0589.2016. |
|
动态评分
0.0