GSK2636771
目录号 : GC17109
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。
Cas No.:1372540-25-4
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
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]。
| 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. |
|
| Cas No. | 1372540-25-4 | SDF | |
| 化学名 | 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-morpholin-4-ylbenzimidazole-4-carboxylic acid | ||
| Canonical 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 |
| 溶解度 | ≥ 10.825mg/mL in DMSO | 储存条件 | 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℃，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。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.3072 mL | 11.5362 mL | 23.0723 mL |
| 5 mM | 0.4614 mL | 2.3072 mL | 4.6145 mL |
| 10 mM | 0.2307 mL | 1.1536 mL | 2.3072 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet