| 名稱(chēng) | Regorafenib monohydrate |
| 描述 | Regorafenib Monohydrate is a novel oral multikinase inhibitor with IC50 values of 13, 4.2, 46, 22, 7, 1.5, 2.5, 28, 19 nM for VEGFR1, murine VEGFR2, murine VEGFR3, PDGFR-β, KIT, RET, RAF-1, B-RAF and B-RAF(V600E) respectively. |
| 細(xì)胞實(shí)驗(yàn) | Each cell line was seeded at 0.3×10^5 cells/2ml of DMEM containing 10% FBS in 35 mm tissue culture dishes. The cells were incubated for 24 h to allow attachment, and then the medium was replaced by fresh culture medium containing Regorafenib at increasing concentrations (1 μM, 2.5 μM, 5 μM, 7.5 μM and 10 μM). In these experimental conditions, the cells were allowed to grow for 72 or 96 h.Time-course experiments on Hep3B cells were performed with 7.5 μM of Regorafenib at short (15, 60, 180 min.), middle (24, 48, 72 and 96 h) or long times (up to seven days). When the cells were treated for long times the drug was replaced with a fresh one. Each experiment included a control with the equivalent concentration of DMSO (solvent control) as the one used for adding Regorafenib. Each experiment was performed in triplicate and repeated 3 times. Subsequent analyses were performed at specific Regorafenib concentrations and incubation times [2].
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| 激酶實(shí)驗(yàn) | In vitro assays using recombinant VEGFR2 (murine aa785–aa1367), VEGFR3 (murine aa818–aa1363), PDGFR-b (aa561–aa1106), RAF-1 (aa305–aa648) and BRAFV600E (aa409–aa765) kinase domains were performed as previously described. Initial in vitro kinase inhibition profiling was performed at a fixed 1 μM compound concentration under Millipore standard conditions [10 μM adenosine-50’- triphosphate (ATP) concentration]. Inhibitory concentration of 50% (IC50) values were determined from selected responding kinases, e.g., VEGFR1 and RET. TIE2 kinase inhibition was measured with a homogeneous time-resolved fluorescence (HTRF) assay using a recombinant fusion protein of glutathione-S-transferase, the intracellular domain of TIE2 and the peptide biotin-Ahx-EPKDDAYPLYSDFG as substrate.
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| 動(dòng)物實(shí)驗(yàn) | Female athymic NCr nu/nu mice, kept in accordance with Federal guidelines, were subcutaneously inoculated with 5×10^6 Colo-205 or MDAMB-231 cells or implanted with 1 mm^3 786-O tumor fragments. When tumors reached a volume of ~100 mm^3, regorafenib or vehicle control was administered orally qd×21 in the 786-O model, and qd×9 in the Colo-205 and MDA-MB231 models, respectively, at doses of 100, 30, 10, and 3 mg/kg. Paclitaxel was administered intravenously at 10 mg/kg in ethanol/Cremophor ELV/saline (12.5%/12.5%/75%) every 2 days×5. Tumor size (volume) was estimated twice weekly (l×w^2)/2, and the percentage of tumor growth inhibition (TGI) was obtained from terminal tumor weights (1-T/C100). Mice were weighed every other day starting from the first day of treatment. The general health status of the mice was monitored daily [1].
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| 體外活性 | Regorafenib有效抑制了包括血管生成和基質(zhì)RTKs VEGFR1-3、TIE2、FGFR1及PDGFR-b在內(nèi)的一系列特定激酶（IC50s：4-311 nM），以及癌變RTKs KIT和RET，還有細(xì)胞內(nèi)信號(hào)激酶c-RAF/RAF-1、BRAF及其V600E變異體（IC50s：1.5-28 nM）。此外，Regorafenib在NIH-3T3/VEGFR2細(xì)胞中強(qiáng)效抑制VEGFR2自磷酸化（IC50：3 nM）。在HAoSMCs中，Regorafenib 經(jīng)PDGF-BB刺激后抑制PDGFR-b自磷酸化（IC50：90 nM）[1]。Regorafenib導(dǎo)致Hep3B細(xì)胞生長(zhǎng)濃度依賴(lài)性下降（IC50：5 μM）。PLC/PRF/5細(xì)胞對(duì)Regorafenib的響應(yīng)與Hep3B細(xì)胞相似，但HepG2細(xì)胞更敏感（IC50：1 μM）[2]。 |
| 體內(nèi)活性 | 給帶瘤大鼠單次口服regorafenib 10 mg/kg可顯著降低腫瘤灌注和對(duì)比劑的滲出。regorafenib處理后10小時(shí)，歸一化的IAUC360顯著降低，并持續(xù)至2天，與對(duì)照組相比。regorafenib通過(guò)口服每日一次（qd）的劑量依賴(lài)方式抑制了在多種異種移植模型中的腫瘤生長(zhǎng)，包括來(lái)自CRC（Colo-205）、BC（MDA-MB-231）和RCC（786-O）腫瘤的模型。regorafenib (10–100 mg/kg)有效抑制了Colo-205異種移植體的生長(zhǎng)，在10 mg/kg劑量時(shí)，第14天的腫瘤生長(zhǎng)抑制（TGI）達(dá)到約75%[1]。在小鼠異種移植模型中，口服regorafenib、M-2和M-5與對(duì)照相比顯著抑制了腫瘤的生長(zhǎng)。小鼠反復(fù)口服regorafenib 10 mg/kg/day后，M-2和M-5在小鼠體內(nèi)的總峰值血漿化合物濃度和暴露程度與人類(lèi)相當(dāng)[3]。 |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 20 mg/mL (39.93 mM)
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| 關(guān)鍵字 | tumor | Colo-205 | HUVECs | PDGFR | NIH-3T3 | Regorafenib monohydrate | inhibit | Raf kinases | antiangiogenic | Regorafenib Monohydrate | Hep3B cell | Autophagy | HAoSMCs | Vascular endothelial growth factor receptor | Inhibitor | Antitumorigenic | 786-O | Regorafenib | Raf | Platelet-derived growth factor receptor | VEGFR | RET | BAY 73-4506 |
| 相關(guān)產(chǎn)品 | Oxyresveratrol | Guanidine hydrochloride | Naringin | Taurine | Gefitinib | Hydroxychloroquine | Curcumin | Stavudine | Paeonol | Sodium 4-phenylbutyrate |
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