GlpBio

GSK2636771

目录号: GC17109纯度: >99.50%
GSK2636771 是一种有效的三磷酸腺苷竞争性口服 PI3Kβ 抑制剂，对催化亚基 p110β 的 IC50 为 5.2 nmol/L，同时比 p110α 和 p110γ 显示出 >900 倍的选择性和 >10 倍的选择性p110δ.用 p110β 抑制剂 GSK2636771 和 AZD6482 处理 72 小时后，对照细胞 的细胞活力明显低于 PTEN 突变体和 PTEN野生型 EEC 细胞。
GSK2636771
Cas No.: 1372540-25-4
规格价格库存数量操作
5mg¥525.00现货
1
10mg¥1,008.00现货
1
50mg¥2,510.00现货
1
100mg¥3,875.00现货
1
10mM (in 1mL DMSO)¥672.00现货
1
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产品描述 Description

GSK2636771 is a potent adenosine triphosphate competitive oral inhibitor of PI3Kβ, with an IC50 of 5.2 nmol/L against the catalytic subunit, p110β, whilst showing >900-fold selectivity over p110α and p110γ, and >10-fold selectivity over p110δ[3,4].

Upon 72 hours treatment with the p110β inhibitors GSK2636771 and AZD6482, cell viability was significantly more decreased in the control cells [ p110β-reliant PTEN-deficient PC3 prostate and BT549 and HCC70 breast cancer cell lines] than in PTEN-mutant and PTEN wild-type EEC cells[1]. GSK2636771 showed a certain inhibitory effect on several CRPC cell lines including C4-2B cell sublines, and BL140 showed a stronger inhibitory effect than GSK2636771[6].

Inhibition of ER/p110β or ER/p110α/βby GSK2636771 induced rapid tumor regression, whereas ER/p110α inhibition had no significant early effect on growth compared to continued ER inhibition alone[2]. To explore the therapeutic potential of simultaneously targeting Cx43 and PIK3CB/p110β, αCT1 is combined with TGX-221 or GSK2636771, two PIK3CB/p110β-selective inhibitors. These two different treatments synergistically inactivate PI3K and sensitize glioblastoma cells to temozolomide in vitro and in vivo[5]. Combining anti-OX40 with GSK2636771, a PI3Kβ-selective inhibitor, delayed tumor growth and extended the survival of mice with PTEN-null melanomas[7].

References:
[1]. Weigelt B, Warne PH, et,al. PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Clin Cancer Res. 2013 Jul 1;19(13):3533-44. doi: 10.1158/1078-0432.CCR-12-3815. Epub 2013 May 14. PMID: 23674493; PMCID: PMC3700760.
[2]. Hosford SR, Dillon LM, et,al. Combined Inhibition of Both p110α and p110β Isoforms of Phosphatidylinositol 3-Kinase Is Required for Sustained Therapeutic Effect in PTEN-Deficient, ER+ Breast Cancer. Clin Cancer Res. 2017 Jun 1;23(11):2795-2805. doi: 10.1158/1078-0432.CCR-15-2764. Epub 2016 Nov 30. PMID: 27903677; PMCID: PMC5449270.
[3]. Janku F, Yap TA, et,al. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018 May;15(5):273-291. doi: 10.1038/nrclinonc.2018.28. Epub 2018 Mar 6. PMID: 29508857.
[4]. Mateo J, Ganji G, et,al. A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2017 Oct 1;23(19):5981-5992. doi: 10.1158/1078-0432.CCR-17-0725. Epub 2017 Jun 23. PMID: 28645941.
[5]. Pridham KJ, Shah F, et,al. Connexin 43 confers chemoresistance through activating PI3K. Oncogenesis. 2022 Jan 12;11(1):2. doi: 10.1038/s41389-022-00378-7. PMID: 35022385; PMCID: PMC8755794.
[6]. He C, Duan S, et,al. Characterization of a novel p110β-specific inhibitor BL140 that overcomes MDV3100-resistance in castration-resistant prostate cancer cells. Prostate. 2017 Aug;77(11):1187-1198. doi: 10.1002/pros.23377. Epub 2017 Jun 20. PMID: 28631436; PMCID: PMC5527967.
[7]. Peng W, Williams LJ,et,al. Anti-OX40 Antibody Directly Enhances The Function of Tumor-Reactive CD8+ T Cells and Synergizes with PI3Kβ Inhibition in PTEN Loss Melanoma. Clin Cancer Res. 2019 Nov 1;25(21):6406-6416. doi: 10.1158/1078-0432.CCR-19-1259. Epub 2019 Aug 1. PMID: 31371342; PMCID: PMC7232853.

GSK2636771 是一种有效的三磷酸腺苷竞争性口服 PI3Kβ 抑制剂，对催化亚基 p110β 的 IC50 为 5.2 nmol/L，同时比 p110α 和 p110γ 显示出 >900 倍的选择性和 >10 倍的选择性p110δ[3,4].

用 p110β 抑制剂 GSK2636771 和 AZD6482 处理 72 小时后，对照细胞 [p110β 依赖性 PTEN 缺陷型 PC3 前列腺癌细胞系以及 BT549 和 HCC70 乳腺癌细胞系] 的细胞活力明显低于 PTEN 突变体和 PTEN野生型 EEC 细胞[1]。 GSK2636771对包括C4-2B细胞亚系在内的几种CRPC细胞系均表现出一定的抑制作用，其中BL140表现出比GSK2636771更强的抑制作用[6]。

GSK2636771 抑制 ER/p110β 或 ER/p110α/β 可诱导肿瘤快速消退，而与单独持续抑制 ER 相比，ER/p110α 抑制对生长没有显着的早期影响[2]。为了探索同时靶向 Cx43 和 PIK3CB/p110β 的治疗潜力，αCT1 与两种 PIK3CB/p110β 选择性抑制剂 TGX-221 或 GSK2636771 联合使用。这两种不同的治疗在体外和体内协同使 PI3K 失活并使胶质母细胞瘤细胞对替莫唑胺敏感[5]。将抗 OX40 与 PI3Kβ 选择性抑制剂 GSK2636771 联合使用可延缓肿瘤生长并延长 PTEN 缺失黑色素瘤小鼠的生存期[7]。

实验参考方法 Experimental Reference Method

Kinase experiment [1]:

Preparation Method

Biochemical selectivity of GSK2636771 was tested using the PI3-Kinase HTRF Assay, as well as the entire panel of GSK in-house kinase selectivity assays. Affinity-enrichment-based chemoproteomics using kinobeads was performed. Briefly, 14 lipid and atypical kinases were enriched from a standard mixture of extracts derived from HeLa, K562, and Jurkat cells using a compound-derivatized bead matrix. The enriched proteins were identified by quantitative mass spectrometry analysis, enabling the simultaneous assessment of binding specificity, and potency for all detected affinity-captured proteins.

Applications

GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ with an apparent Ki value of 0.89 nmol/L (IC50 = 5.2 nmol/L), >900-fold selectivity over p110α and p110γ, and >10-fold selectivity over p110δ isoforms, while sparing other PI3K superfamily kinases.
Cell experiment [2]:

Cell lines

PTEN-deficient PC3 prostate and BT549 and HCC70 breast cancer cell lines

Preparation Method

Cell viability was determined after 72 hours of treatment with indicated concentrations of the p110β selective inhibitors GSK2636771 and AZD6482 in 3 p110β-reliant breast and prostate cancer cell lines, 7 PTEN wild-type EEC cells, and 17 PTEN-mutant EEC cells.

Reaction Conditions

1-10uM GSK2636771 for 72 hours

Applications

Upon 72 hours treatment with the p110β inhibitors GSK2636771 and AZD6482, cell viability was significantly more decreased in the control cells [ p110β-reliant PTEN-deficient PC3 prostate and BT549 and HCC70 breast cancer cell lines] than in PTEN-mutant and PTEN wild-type EEC cells.
Animal experiment [3]:

Animal models

Female athymic nude mice (4-5-week-old)

Preparation Method

Female athymic nude mice were injected subcutaneously with ZR75-1/FR cells resuspended in matrigel. On the same date, mice were implanted subcutaneously with a 17β-estradiol pellet, and fulvestrant treatment was initiated. Four weeks after implantation, tumor-bearing mice were randomized to treatment with vehicle, GSK2636771 (30 mg/kg/d, orally), BYL719, or the combination, all with a fulvestrant treatment backbone.

Dosage form

GSK2636771 (30 mg/kg/d, orally)

Applications

Inhibition of ER/p110β or ER/p110α/βby GSK2636771 induced rapid tumor regression, whereas ER/p110α inhibition had no significant early effect on growth compared to continued ER inhibition alone.

References:

[1]. Mateo J, Ganji G, et,al . A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2017 Oct 1;23(19):5981-5992. doi: 10.1158/1078-0432.CCR-17-0725. Epub 2017 Jun 23. PMID: 28645941.

[2]. Weigelt B, Warne PH, et,al. PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Clin Cancer Res. 2013 Jul 1;19(13):3533-44. doi: 10.1158/1078-0432.CCR-12-3815. Epub 2013 May 14. PMID: 23674493; PMCID: PMC3700760.

[3]. Hosford SR, Dillon LM, et,al . Combined Inhibition of Both p110α and p110β Isoforms of Phosphatidylinositol 3-Kinase Is Required for Sustained Therapeutic Effect in PTEN-Deficient, ER+ Breast Cancer. Clin Cancer Res. 2017 Jun 1;23(11):2795-2805. doi: 10.1158/1078-0432.CCR-15-2764. Epub 2016 Nov 30. PMID: 27903677; PMCID: PMC5449270.

产品文档 Product Documents

Purity:>99.50%

化学性质Chemical Properties

CAS 号
1372540-25-4
化学名
2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-morpholin-4-ylbenzimidazole-4-carboxylic acid
SMILES
CC1=C(C=CC=C1C(F)(F)F)CN2C(=NC3=C2C=C(C=C3C(=O)O)N4CCOCC4)C
分子式
C22H22F3N3O3
分子量
433.42 g/mol
溶解性
≥ 10.825mg/mL in DMSO
保存条件
Store at -20°C
General tips
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；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。
为了提高溶解度，请将管子加热至 37°C，然后在超声波浴中震荡一段时间。
Shipping Condition
评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备 RT，或根据请求配备蓝冰。

计算工具摩尔浓度 / 稀释 / 分子量 / 单位换算 / 体内配方 / 溶解度

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