布帕尼西作用机制 - Medchemexpress - MCE中国

Product Data?SheetBuparlisibCat. No.:CAS No.:分?式:分?量:作?靶点:作?通路:储存?式:HY-70063944396-07-0C??H??F?N?O?410.39PI3K; ApoptosisPI3K/Akt/mTOR; ApoptosisPowderIn solvent-20°C4°C-80°C-20°C3 years2 years6 months1 monthInhibitors?Agonists?Screening Libraries溶解性数据体外实验DMSO : ≥ 100 mg/mL (243.67 mM)* \Mass1 mg5 mg10 mgSolventConcentration制备储备液1 mM5 mM10 mM2.4367 mL0.4873 mL0.2437 mL12.1835 mL2.4367 mL1.2184 mL24.3671 mL4.8734 mL2.4367 mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；?旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存?式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 储存时，请在 6 个?内使?，-20°C 储存时，请在 1 个?内使?。体内实验请根据您的实验动物和给药?式选择适当的溶解?案。以下溶解?案都请先按照 In Vitro ?式配制澄清的储备液，再依次添加助溶剂： 为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的?作液，建议您现?现配，当天使?； 以下溶剂前显?的百分?是指该溶剂在您配制终溶液中的体积占?；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的?式助溶1. 请依序添加每种溶剂：?10% DMSO ?? 40% PEG300 ?? 5% Tween-80 ?? 45% salineSolubility: ≥ 2.5 mg/mL (6.09 mM); Clear solution此?案可获得 ≥ 2.5 mg/mL (6.09 mM，饱和度未知) 的澄清溶液。 以 1 mL ?作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加? 50 μL Tween-80，混合均匀；然后继续加? 450 μL ?理盐?定容? 1 mL。2. 请依序添加每种溶剂：?10% DMSO ?? 90% (20% SBE-β-CD in saline)Solubility: ≥ 2.5 mg/mL (6.09 mM); Clear solutionPage 1 of 2 www.MedChemExpress.cn

此?案可获得 ≥ 2.5 mg/mL (6.09 mM，饱和度未知) 的澄清溶液。

以 1 mL ?作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD ?理盐??溶液中，混合均匀。

3. 请依序添加每种溶剂：?10% DMSO ?? 90% corn oilSolubility: ≥ 2.5 mg/mL (6.09 mM); Clear solution

此?案可获得 ≥ 2.5 mg/mL (6.09 mM，饱和度未知) 的澄清溶液，此?案不适?于实验周期在半个?以上的实验。 以 1 mL ?作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL ??油中，混合均匀。

BIOLOGICAL ACTIVITY

?物活性

Buparlisib (BKM120; NVP-BKM120) 是?种 pan-class I PI3K 抑制剂，作?于 p110α/p110β/p110δ/p110γ，IC50 分别为 52 nM/166 nM/116 nM/262 nM。

IC?? & Target

p110α52 nM (IC50)p110β166 nM (IC50)

体外研究

p110α-H1047R58 nM (IC50)p110γ262 nM (IC50)

p110α-E545K99 nM (IC50)Vps342.4 μM (IC50)

p110δ116 nM (IC50)mTOR4.6 μM (IC50)

Buparlisib (NVP-BKM120) exhibits 50-300 nM activity for class I PI3K’s, including the most common p110α mutants. Additionally, NVP-BKM120 exhibits lower potency against class III and class IV PI3K's, where 2, 5, >5, and >25 μM biochemical activity is observed for inhibition of VPS34, mTOR, DNAPK, and PI4K, respectively[1]. Buparlisib (NVP-BKM120) induces multiple myeloma (MM) cell apoptosis in both dose- and time-dependent manners. Buparlisib (NVP-BKM120) at concentrations ≥10 μM induces significant apoptosis in all tested MM cell lines at 24 h (P<0.05, compares with control). Therefore, 10 μM Buparlisib (NVP-BKM120) and 24-h treatment are chose in in the following experiments if not stated otherwise. Buparlisib (NVP-BKM120) treatment results in a dose-dependent growth inhibition in all tested MM cell lines. Buparlisib (NVP-BKM120) IC50 varies among tested MM cells. At 24 h treatment, IC50 for ARP-1, ARK, and MM.1R is between 1 and 10 μM, while IC50 for MM.1S is <1 μM, and IC50 for U266 is between 10 and 100 μM. In summary, NVP-BKM120 treatment results in MM cell growth inhibition and apoptosis in dose- and time-dependent manners[2].

体内研究

In A2780 xenograft tumors, oral dosing of Buparlisib (NVP-BKM120) at 3, 10, 30, 60, and 100 mg/kg results in a dose dependent modulation of pAKTSer473. Partial inhibition of pAKTSer473 is observed at 3 and 10 mg/kg, and near complete inhibition is observed at doses of 30, 60, or 100 mg/kg, respectively. Inhibition of pAKT (normalized to total AKT) tracked well with both plasma and tumor drug exposure[1]. Mice receiving Buparlisib (NVP-BKM120) (5 μM per kg per day for 15 days) treatment has significantly smaller tumor burdens as compare with control mice, which are measured as tumor volume (P<0.05) and level of circulating human kappa chain (P<0.05). In addition, NVP-BKM120 treatment significantly prolongs the survival of tumor-bearing mice (P<0.05)[2].

PROTOCOL

Cell Assay [1]

A2780 cells are cultured in DMEM supplemented with 10% FBS. L-glutamine, sodium pyruvate, and antibiotics. Cells are plated in the same medium at a density of 1000 cells per well, 100 uL per well into black-walled-clear-bottom plates and incubated for 3-5 hours. Buparlisib (NVP-BKM120) supplied in DMSO (20 mM) are diluted further into DMSO (7.5 uL of 20 mM Buparlisib (NVP-BKM120) in 22.5 uL DMSO. Mix well, transfer 10 uL to 20 uL DMSO, repeat until 9 concentrations have been made). The diluted Buparlisib (NVP-BKM120) solution (2 uL), is then added to cell medium (500 uL) cell medium. Equal volumes of this solution (100 uL) are added to the cells in 96 well plates and

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incubated at 37oC for 3 days and developed using Cell Titer Glo. Inhibition of cell proliferation is determined by luminescence read using Trilux[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal

Administration [2]

Mice[2]

Six- to eight-week-old female severe combined immunodeficiency (SCID) mice are used. SCID mice are subcutaneously inoculated in the right flank with 1 million ARP-1 or MM.1S cells suspended in 50 μL phosphate-buffered saline (PBS). After palpable tumor developed (tumor diameter ≥5 mm), mice are treated with intraperitoneal injection of DMSO/PBS or Buparlisib (NVP-BKM120) (5 μM per kg per day) for 15 days. Tumor sizes are measured every 5 days, and blood samples are collected at the same period. Tumor burdens are evaluated by measuring tumor size and detecting circulating human kappa chain or lambda chain.

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

客户使?本产品发表的科研?献

????Nature. 2018 Aug;560(7719):499-503.????Nat Med. 2016 Jul;22(7):723-6.

????Cancer Discov. 2019 Sep;9(9):1306-1323.????Cancer Discov. 2018 Mar;8(3):354-369.

????Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093.See more customer validations on www.MedChemExpress.cnREFERENCES

[1].?Burger MT, et al. Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer. ACS Med Chem Lett. 2011 Aug 26;2(10):774-9.

[2].?Zheng Y, et al. Novel phosphatidylinositol 3-kinase inhibitor NVP-BKM120 induces apoptosis in myeloma cells and shows synergistic anti-myeloma activity. J Mol Med (Berl). 2012 Jun;90(6):695-706.

[3].?Ni J, et al. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med. 2016 Jul;22(7):723-6.

[4].?Liu H, et al. Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple Negative Breast Cancer. Cancer Discov. 2018 Mar;8(3):354-369.

McePdfHeightCaution: Product has not been fully validated for medical applications. For research use only.

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