| 名稱 | Buparlisib |
| 描述 | Buparlisib (BKM120) is an orally bioavailable specific oral inhibitor of the pan-class I PI3K (IC50s: 52/166/116/nM for p110α, p110β, and p110δ). |
| 細胞實驗 | A2780 cells were cultured in DMEM supplemented with 10% FBS. L-glutamine, sodium pyruvate, and antibiotics. Cells were 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. Test compounds supplied in DMSO (20 mM) were diluted further into DMSO (7.5 ul of 20 mM test compound in 22.5 ul DMSO. Mix well, transfer 10 ul to 20 ul DMSO, repeat until 9 concentrations have been made). The diluted test compound solution (2uL), was then added to the cell medium (500 ul) cell medium. Equal volumes of this solution (100 uL) were added to the cells in 96 well plates and incubated at 37 oC for 3 days and developed using Cell Titer Glo. Inhibition of cell proliferation was determined by luminescence read using Trilux [1]. |
| 激酶實驗 | Compounds to be tested were dissolved in DMSO and directly distributed into a black 384-well plate at 1.25 μL per well. To start the reaction, 25 μL of 10 nM PI3 kinase and 5 μg/mL 1-alpha-phosphatidylinositol (PI) in assay buffer (10 mM Tris pH 7.5, 5 mM MgCl2, 20 mM NaCl, 1 mM DTT and 0.05% CHAPS) were added into each well followed by 25 μL of 2 μM ATP in assay buffer. The reaction was performed until approx 50% of the ATP was depleted, and then stopped by the addition of 25 μL of KinaseGlo solution. The stopped reaction was incubated for 5 minutes and the remaining ATP was then detected via luminescence [1]. |
| 動物實驗 | Six- to eight-week-old female severe combined immunodeficiency (SCID) mice were housed and monitored in the MD Anderson Cancer Center animal research facility. SCID mice were 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 were treated with intraperitoneal injection of DMSO/PBS or BKM120 (5 μM per kg per day) for 15 days. Tumor sizes were measured every 5 days, and blood samples were collected at the same period. Tumor burdens were evaluated by measuring tumor size and detecting the circulating human kappa chain or lambda chain [3]. |
| 體外活性 | Buparlisib對類I PI3K（包括常見的p110R突變體）表現(xiàn)出50-300 nM的活性。此外，其對類III和類IV PI3K的抑制活性較低，分別觀察到VPS34、mTOR、DNAPK和PI4K的生化活性在2、5、>5和>25 μM。在所有細胞系中，通路調節(jié)和抗增殖活性與細胞內PI3K抑制一致[1]。Buparlisib在11種人類胃癌細胞系中展現(xiàn)出抗增殖活性，通過減少mTOR下游信號傳導。但是Buparlisib處理通過穩(wěn)定胰島素受體底物-1來取消反饋抑制，從而增加了p-AKT。在KRAS突變型胃癌細胞中，處理Buparlisib后，p-ERK或p-STAT3也有所增加[2]。BKM120在多個骨髓瘤（MM）細胞系和新鮮分離的初級MM細胞中誘導細胞生長抑制和凋亡。此外，BKM120與地塞米松在對地塞米松敏感的MM細胞中顯示出協(xié)同細胞毒性。低劑量的BKM120和地塞米松，各自獨立具有有限的細胞毒性，能在MM.1S和ARP-1中誘導顯著的細胞凋亡。BKM120暴露導致通過上調p27 (Kip1)和下調cyclin D1來引發(fā)細胞周期阻滯，并通過下調抗凋亡的XIAP和上調表達細胞毒性小型異構體BimS來誘發(fā)依賴于半胱天冬酶的凋亡[3]。 |
| 體內活性 | 在A2780異種移植瘤模型中，口服Buparlisib以3、10、30、60及100 mg/kg劑量對pAKTSer473進行了劑量依賴性調節(jié)。在3及10 mg/kg劑量時觀察到pAKTser473的部分抑制；而在30、60或100 mg/kg劑量時，則觀察到幾乎完全抑制。pAKT的抑制與血漿及腫瘤內化合物暴露程度密切相關。pAKT調節(jié)同樣依賴于時間，當血漿和腫瘤暴露量大約為2 μM時，在10小時時間點，60及100 mg/kg劑量實現(xiàn)了>90%的靶點調節(jié)[1]。與對照組小鼠相比，每天以5 μM/kg劑量Buparlisib治療的小鼠顯示出明顯較小的腫瘤負擔，此負擔通過腫瘤體積和循環(huán)人類κ鏈水平來衡量。此外，Buparlisib治療顯著延長了負載瘤小鼠的生存期[3]。 |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 76 mg/mL (185.19 mM), Sonication is recommended.
H2O : Insoluble
Ethanol : 2 mg/mL (4.87 mM), Sonication is recommended.
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| 關鍵字 | Vps34 | PI3K | Phosphoinositide 3-kinase | p110δ | p110γ | p110β | p110α | NVP-BKM-120 | NVP-BKM 120 | Inhibitor | inhibit | Buparlisib | BKM-120 | BKM 120 | Apoptosis |
| 相關產品 | L-Glutamic acid | Cysteamine hydrochloride | Alginic acid | Flubendazole | 5-Fluorouracil | Stavudine | Dextran sulfate sodium salt (MW 4500-5500) | Tributyrin | Myricetin | L-Ascorbic acid sodium salt | L-Ascorbic acid | Sodium 4-phenylbutyrate |
| 相關庫 | 抑制劑庫 | 經典已知活性庫 | 抗癌活性化合物庫 | 已知活性化合物庫 | 臨床失敗化合物庫 | 激酶抑制劑庫 | 神經再生化合物庫 | 抗衰老化合物庫 | 免疫/炎癥分子化合物庫 | 藥物功能重定位化合物庫 | 抗癌臨床化合物庫 | 抗癌藥物庫 |