XL147 analogue

製品コードS1118 バッチS111805

印刷

化学情報

 Chemical Structure Synonyms SAR245408 Storage
(From the date of receipt)
3 years -20°C powder
1 years -80°C in solvent
化学式

C21H16N6O2S2

分子量 448.52 CAS No. 956958-53-5
Solubility (25°C)* 体外 DMSO 90 mg/mL (200.65 mM)
Water Insoluble
Ethanol Insoluble
体内 (毎回新しく調製した物を用意してください)
Clear solution
30%PEG400 0.5%Tween80 5%propylene glycol
15.0mg/ml Taking the 1 mL working solution as an example, add 300 μL of 50 mg/ml clarified PEG400 stock solution to 5 μL of Tween80, mix evenly to clarify it; add 50 μL Propylene glycol to the above system, mix evenly to clarify it; then continue to add 645 μL ddH2O to adjust the volume. to 1 mL. The mixed solution should be used immediately for optimal results. 
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液(一定の濃度)を調合する

生物活性

製品説明 XL147 analogue (SAR245408) is a selective and reversible class I PI3K inhibitor for PI3Kα/δ/γ with IC50 of 39 nM/36 nM/23 nM in cell-free assays, less potent to PI3Kβ. XL147 analogue induces apoptosis. Phase 1/2.
in vitro XL147 inhibits class I PI3K isoforms in an ATP-competitive manner. In a panel of HER2-overexpressing human breast cancer cell lines, treatment with XL147 abrogates AKT and S6 phosphorylation but also induces the expression and phosphorylation of HER3 and other RTKs. In HER2+ cells, phosphorylation of HER3 is maintained by the HER2 tyrosine kinase, leading to partial recovery of phosphorylated AKT (pAKT) and thereby limiting the antitumor action of XL 147. In addition, knockdown of HER3 or treatment with the anti-HER2 agents trastuzumab or lapatinib sensitizes HER2+ breast cancer cells to XL147 in vitro and in vivo. Treatment with XL147 inhibits the monolayer growth of all tested cell lines, including BT474, HCC1937 et al. in a dose-dependent manner. The main effect of XL147 is inhibition of cell proliferation. XL147 induces cell death at the concentration of 20 μM. Treatment with XL147 leads to dose-dependent inhibition of PI3K. Consistent with the inhibition of cell proliferation, XL147 induces a reduction in cyclin D1 and pRB and an increase in levels of the CDK inhibitor p27KIPI but no detectable change in levels off total or cleaved poly (ADP-ribose) polymerase (PARP). Treatment with XL147 leads to a dose-dependent reduction in pAKTS473/T308 and pS6S240/244. Surprisingly, XL147 also triggers up-regulation of total HER3 and/or pHER3Y1289 levels. In HER2-overexpressing cells, inhibition of PI3K is followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors prevents the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2+ cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhances XL147-induced cell death and inhibition of pAKT and pS6. [2]
in vivo Athymic mice with BT474 xenografts are randomly treated with XL147, lapatinib, trastuzumab, or XL147 plus each HER2 antagonist. Each monotherapy significantly inhibtis tumor growth with trastuzumab being the only agent that induced a complete tumor regression in one of eight mice. Both combinations are superior to the respective drugs given alone. Notably, the combination of trastuzumab and XL147, but not lapatinib and XL147, induces a complete tumor response in three of eight mice. There is no marked drug-related toxicity in any of the treatment arms. The combination of XL147 plus trastuzumab prevents pHER3 more potently than any of the other treatments. In good agreement with differences in tumor growth among treatment arms, nuclear pAKT is lower in tumors treated with XL147 plus lapatinib or XL147 plus trastuzumab compared with tumors treated with single agents. Of all three single drugs, XL147 is the only one shown statistically to repress nuclear pAKT levels. There are no detectable changes in cytoplasmic pAKT levels. Combined inhibition of HER2 and PI3K in HER2-dependent xenografts is required to maximally inhibit signaling output of the PI3K/AKT pathway. [2]

プロトコル(参考用のみ)

細胞アッセイ 細胞株 BT474 and HCC1937 cells
濃度 0-20 μM
反応時間 72 hours
実験の流れ

Cells including BT474, HCC1937 et al. are seeded in 100-mm dishes in media containing 2.5% FBS with or without XL147. After 3 days, detached and adherent cells are pooled, fixed, and labeled with propidium iodide by using the APO-BrdU kit. Labeled cells are analyzed using the Becton Dickinson FACSCalibur system.

動物実験 動物モデル Athymic female mouse bearing BT474 cells
投薬量 100 mg/kg
投与方法 Orogastric gavage

カスタマーフィードバック

Data independently produced by Dr. Zhang of Tianjin Medical University ,

, , Dr. Chunrong Yu of RoswelI Park Cancer Institute

Selleckの高級品が、幾つかの出版された研究調査結果(以下を含む)で使われた:

Establishment and Characterization of NCC-PMP1-C1: A Novel Patient-Derived Cell Line of Metastatic Pseudomyxoma Peritonei [ J Pers Med, 2022, 12(2)258] PubMed: 35207746
Establishment and characterization of NCC-UPS4-C1: a novel cell line of undifferentiated pleomorphic sarcoma from a patient with Li-Fraumeni syndrome [ Hum Cell, 2022, 10.1007/s13577-022-00671-y] PubMed: 35118583
Establishment and characterization of novel patient-derived cell lines from giant cell tumor of bone [ Hum Cell, 2021, 10.1007/s13577-021-00579-z] PubMed: 34304386
Establishment and characterization of the NCC-GCTB4-C1 cell line: a novel patient-derived cell line from giant cell tumor of bone [ Hum Cell, 2021, 10.1007/s13577-021-00639-4] PubMed: 34731453
Establishment and characterization of NCC-MFS4-C1: a novel patient-derived cell line of myxofibrosarcoma [ Hum Cell, 2021, 34(6):1911-1918] PubMed: 34383271
Establishment and characterization of NCC-MFS2-C1: a novel patient-derived cancer cell line of myxofibrosarcoma [ Hum Cell, 2020, 10.1007/s13577-020-00420-z] PubMed: 32870449
hMENA11a contributes to HER3-mediated resistance to PI3K inhibitors in HER2-overexpressing breast cancer cells. [Trono P,et al. Oncogene, 2015, 10.1038/onc.2015.143] PubMed: 25961924
Quantitative optical imaging of primary tumor organoid metabolism predicts drug response in breast cancer [Walsh AJ, et al Cancer Res, 2014, 74(18):5184-94] PubMed: 25100563
Deciphering combinations of PI3K/AKT/mTOR pathway drugs augmenting anti-angiogenic efficacy in vivo [ PLoS One, 2014, 9(8):e105280] PubMed: 25144531
Deciphering Combinations of PI3K/AKT/mTOR Pathway Drugs Augmenting Anti-Angiogenic Efficacy In Vivo [Sasore T, et al PLoS One, 2014, 9(8):e105280] PubMed: 25144531

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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