Product Introduction
Bioactivity


英文名: Derazantinib

描述: Derazantinib (ARQ-087) 是一種有效的，ATP 競爭型的，具有口服活性的酪氨酸激酶抑制劑，能夠抑制軟骨細胞FGFR1 (IC50:4.5 nM)、FGFR2 (IC50:1.8 nM)、FGFR3 (IC50:4.35nM)。

細胞實驗: Cells are seeded at 3000-5000 cells per well with 130 μL media in 96-well tissue culture-treated plates. The cells are incubated overnight and subsequently treated with 3-fold serial dilutions of Derazantinib starting at 100 μM. The cells are returned to a 37°C humidified incubator for 72 hours. Cell proliferation is measured using the MTS assay [1].

激酶實驗: Derazantinib is titrated in DMSO utilizing a 3-fold dilution scheme and then diluted 10-fold further in deionized water for a final DMSO concentration of 10%. A volume (2.5 μL) of these dilutions or vehicle is added to each well of a reaction plate. FGFR1 or FGFR2 is added to assay buffer to each well in a volume of 17.5 μL for a final concentration of 0.50 or 0.25 nM, respectively. After a 30-minute pre-incubation period, ATP and substrate are added in assay buffer (5 μL) for final concentrations of 0-1,000 μM ATP and 80 nM biotinylated-PYK2, for a final reaction volume of 25 μL. The plates are incubated for 60 minutes at room temperature and then stopped in the dark by the addition of 10 μL stop/detection mixture prepared in assay buffer containing EDTA [1].

動物實驗: Female NCr nu/nu mice (SNU-16) or CB17 SCID mice (NCI-H716) with well established (400 mg) subcutaneous tumors are given a single oral dose of Derazantinib or vehicle control. Plasma and tumor samples are collected 4 hours post single dose. Derazantinib is administered orally. The dosing volume for all groups is 10 mL/kg or 0.1 mL/10 g body weight [1].

體外活性: 在細胞中，通過對Derazantinib的響應(yīng)，明顯可以看到FGFR2自磷酸化及FGFR途徑下游其它蛋白質(zhì)(FRS2α, AKT, ERK)的抑制。Derazantinib對于因FGFR失調(diào)（包括擴增、融合和突變）而增殖的細胞系具有抗增殖作用。在高水平表達FGFR2蛋白的細胞系的細胞周期研究中，Derazantinib誘導的G1期細胞周期阻滯與后續(xù)的凋亡誘導之間存在正相關(guān)[1]。Derazantinib能夠在EC50約為100 nM時，解救FGF2介導的生長停滯，且在高達500 nM的濃度下沒有顯著毒性。在70-500 nM的濃度范圍內(nèi)，Derazantinib顯著抑制FGF2的效應(yīng)。Derazantinib抑制FGF介導的細胞外基質(zhì)喪失與軟骨細胞過早衰老的誘導，并在脛骨培養(yǎng)中解救FGF介導的軟骨細胞分化抑制。在無細胞激酶試驗中，Derazantinib抑制FGFR1-4但不抑制其他受體酪氨酸激酶。Derazantinib還能抑制與顱縫早閉癥相關(guān)的FGFR1和FGFR2突變[2]。

體內(nèi)活性: Derazantinib在含有FGFR2基因擴增和融合的SNU-16及NCI-H716異種移植瘤模型中有效抑制腫瘤生長[1]。在Derazantinib注射的翼部，大多數(shù)胚胎展現(xiàn)出異常的外部表型(81.3%)，這可能是由于抑制了肢芽間充質(zhì)的增殖[2]。

存儲條件: Powder: -20°C for 3 years | In solvent: -80°C for 1 year

溶解度: DMSO : 98 mg/mL (209.15 mM)


關(guān)鍵字: ARQ087 | Fibroblast growth factor receptor | inhibit | FGFR | ARQ 087 | Inhibitor | Derazantinib

相關(guān)產(chǎn)品: Amlexanox | R1530 | SM27 | 2,5-Dihydroxybenzoic acid | Mubritinib | PF 477736 | CHIR-98014 | H3B-6527 | Sulfatinib | Pazopanib Hydrochloride

相關(guān)庫: Drug Repurposing Compound Library | Anti-Cancer Compound Library | Anti-Cancer Drug Library | Membrane Protein-targeted Compound Library | Bioactive Compounds Library Max | Inhibitor Library | Kinase Inhibitor Library | Anti-Cancer Clinical Compound Library | Tyrosine Kinase Inhibitor Library | Anti-Cancer Active Compound Library

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