Zoligratinib

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Chemical Structure| 1265229-25-1 同义名 : Debio 1347;CH5183284;FF284
CAS号 : 1265229-25-1
货号 : A120438
分子式 : C20H16N6O
纯度 : 99%+
分子量 : 356.381
MDL号 : MFCD28502053
存储条件：

Pure form Keep in dark place,Inert atmosphere,Room temperature

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 25 mg/mL(70.15 mM)，配合低频超声，并水浴加热至45℃助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+30% PEG300+water 8 mg/mL clear

PO 0.5% CMC-Na 46 mg/mL suspension

生物活性
靶点

  • FGFR2

    FGFR2, IC50:7.6 nM

  • FGFR3

    FGFR3, IC50:22 nM

  • FGFR4

    FGFR4, IC50:290 nM

  • FGFR1

    FGFR1, IC50:9.3 nM
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].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.81mL

0.56mL

0.28mL

14.03mL

2.81mL

1.40mL

28.06mL

5.61mL

2.81mL
参考文献

[1]Nakanishi Y, Akiyama N, et al. The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor. Mol Cancer Ther. 2014 Nov;13(11):2547-58.