生物活性

• 靶点

  FGFR1 IC50:9.3nM

  FGFR2 IC50:7.6nM

  FGFR3 IC50:22nM

  FGFR4 IC50:290nM

• 描述The FGFR (fibroblast growth factor receptor) family, comprising four members, FGFR1, FGFR2, FGFR3 and FGFR4, belongs to the RTKs which serve as high affinity receptors for FGFs controlling cell proliferation, migration, apoptosis and differentiation. CH5183284 is an FGFR-selective inhibitor with IC50 values of 9.3 nM, 7.6 nM, 22 nM and 290 nM for FGFR1, FGFR2, FGFR3 and FGFR4 (measured by enzyme activity), respectively. CH5183284 can prevent auto-phosphorylation of FGFR1, FGFR2, and FGFR3 at 100 to 300 nM in the DMS114 (FGFR1 amplification), SNU-16 (FGFR2 amplification) and KMS11 [t(4;14) translocation and FGFR3 Y373C mutation] cell lines, with no effect on auto-phosphorylation of FGFR4, KDR, PDGFRα, or c-KIT at the same concentration in MDA-MB-453 (FGFR4 mutation), human umbilical vein endothelial cells (HUVEC), NCIH1703 (PDGFRαamplification) and Kasumi-1 (c-KIT N822K mutation). CH5183284 showed more potent inhibition on FGF- than VEGF-dependent proliferation of HUVECs with IC50 of 29 nM, yet had no inhibition on VEGF-induced tube formation of HUVECs. The selective FGFR inhibition by CH5183284 led to the selective antiproliferative activity against the cancer cells harboring the FGFR genetic alterations, including CNV of FGFR1, FGFR1OP-FGFR1, CNVs of FGFR2, FGFR2 (S252W, K310R, N549K), FGFR3-TACC3, FGFR3-BAIAP2L1 and FGFR3 (S249C, Y373C). Oral treatment with CH5183284 at concentration of 10, 30 and 100 mg/kg daily for 11 days caused tumor growth inhibition in a dose-dependent manner in mice bearing KG1, SNU-16, MFE280, UM-UC-14 and RT112/84 harboring the FGFR genetic alterations, but no effect on MKN-45 (cells with MET amplification) xenografted mice. Consistent with in vitro assays, suppression of p-FGFR for at least 7 hours, as well as the downstream signaling, as indicated by a reduction in phospho-FRS, phospho-ERK, and phospho-S6 by CH5183284 can be observed in SNU-16 xenografted tissue^[1].
• 作用机制CH5183284 is an ATP-competitive inhibitor through interaction with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3^[1].

• 动物研究
  剂量	Mice[1] (p.o.): 10 mg/kg - 100mg/kg
  给药途径	p.o.
  动物药代数据	Animal Rats[1] Dose 30 mg/kg Administration p.o. AUC 102 mg/h·ml