CCT128930 是一种 ATP 竞争性地且选择性的AKT抑制剂 (对AKT2 的IC50为 6 nM )。CCT128930 通过靶向 AKT 的 Met282 (PKA-AKT嵌合体的 Met173),对 PKA 激酶 (IC50=168 nM) 具有 28 倍的选择性,对 p70S6K (IC50=120 nM) 具有 20 倍的选择性。具有抗肿瘤活性。
生物活性 | CCT128930 is a ATP-competitive and selective inhibitor ofAKT(IC50=6 nM for AKT2). CCT128930 has 28-fold selectivity over the closely relatedPKAkinase (IC50=168 nM) through the targeting of Met282 ofAKT(Met173 of PKA-AKT chimera), as well as 20-fold selectivity overp70S6K(IC50=120 nM). Antitumor activity. |
IC50& Target[1] | Akt2 6 nM (IC50) | p70S6K 120 nM (IC50) | PKA 168 nM (IC50) | Autophagy | Apoptosis |
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体外研究 (In Vitro) | The GI50values of CCT128930 for growth inhibition are 6.3 μM for U87MG human glioblastoma cells, 0.35 μM for LNCaP human prostate cancer cells, and 1.9 μM for PC3 human prostate cancer cells, all of which are PTEN-deficient human tumor cell lines[1]. CCT128930 (0.1-60 μM; 1 hour; U87MG human glioblastoma cells) shows an initial induction of AKT phosphorylation at serine 473 up to 20 μM, followed by a decreased in phosphorylation at higher concentrations[1]. CCT128930 inhibits direct substrates of AKT (Ser9 GSK3β, pThr246 PRAS40 and pT24 FOXO1/p32 FOXO3a) at ≥5 μM, and the downstream target, pSer235/236 S6RP at ≥ 10 μM, with generally constant levels of the respective total proteins and GAPDH[1]. CCT128930 (18.9 μM; U87MG human glioblastoma cells) causes an increase in phosphorylation of pSer473 AKT after 30 minutes, which is sustained for 48 hours. Total AKT protein signal decreases gradually from 8 hours to 48 hours of treatment[1]. CCT128930 (PTEN-null U87MG human glioblastoma cells; over a 24-hour time period) results in an increase in G0/G1 phase cells from 43.6% to 64.8% after 24 hours of treatment[1]. CCT128930 (0-10 μM; 24 hours) increases, but not inhibites, the phosphorylation of Akt in HepG2 and A549 cells. CCT128930 (0-20 μM; 24 hours) inhibits cell proliferation by inducing cell cycle arrest in G1 phase through downregulation of cyclinD1 and Cdc25A, and upregulation of p21, p27 and p53. CCT128930 (20 μM) triggers cell apoptosis with activation of caspase-3, caspase-9, and PARP. CCT128930 (0-20 μM; 24 hours) increases phosphorylation of ERK and JNK in HepG2 cells. CCT128930 (0-20 μM; 24 hours) activates DNA damage response of HepG2 cell characterized by phosphorylation of H2AX, ATM (ataxia-telangiectasia mutated), Chk1 and Chk2[2].
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体内研究 (In Vivo) | CCT128930 (25 or 40 mg/kg; i.p. daily or twice daily for 5 days) shows antitumor activities in U87MG and BT474 human breast cancer xenografts[1]. Summary of the pharmacokinetic parameters of CCT128930 (25 mg/kg) in CrTacNCr-Fox1numice[1]
Tissue | Route | T1/2 (h) | Tmax (h) | Cmax (μM) | Vss (L) | Cl (L/h) | AUC0-∞ (μMh) | Bioavailability (%) | Plasma | i.v. | 0.95 | 0.083 | 6.36 | 0.25 | 0.325 | 4.62 | 100 | Plasma | i.p. | 2.33 | 0.5 | 1.28 | N/A | 0.372 | 1.33 | 28.8 | Tumor | i.p. | 3.89 | 1 | 8.02 | N/A | 0.06* | 25.8 | N/A | Plasma | p.o. | 0.57 | 0.5 | 0.432 | N/A | 0.317 | 0.392 | 8.5 | *Apparent clearance.
Animal Model: | 6-8 weeks old female CrTacNCr-Fox1numice[1] | Dosage: | 25 mg/kg (U87MG human glioblastoma xenografts) or 40 mg/kg (BT474 human breast cancer xenografts) | Administration: | i.p. daily for 5 days (U87MG human glioblastoma xenografts); i.p. twice daily for 5 days (BT474 human breast cancer xenografts) | Result: | Giving a treated:control (T/C) ratio on day 12 of 48%. There was no weight loss associated with this regime in U87MG human glioblastoma xenografts. Had a profound antitumor effect with complete growth arrest and a T/C ratio of 29% on day 22. This regimen was associated with minimal weight loss, with a nadir of only 94.8% of the initial body weight on day 15 of treatment in BT474 human breast cancer xenografts. |
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运输条件 | Room temperature in continental US; may vary elsewhere. |
储存方式 | Powder | -20°C | 3 years | | 4°C | 2 years | In solvent | -80°C | 6 months | | -20°C | 1 month |
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溶解性数据 | In Vitro: DMSO : 33.33 mg/mL(97.50 mM;ultrasonic and warming and heat to 60℃) 配制储备液 1 mM | 2.9253 mL | 14.6267 mL | 29.2535 mL | 5 mM | 0.5851 mL | 2.9253 mL | 5.8507 mL | 10 mM | 0.2925 mL | 1.4627 mL | 2.9253 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;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℃, 6 months; -20℃, 1 month。-80℃ 储存时,请在 6 个月内使用,-20℃ 储存时,请在 1 个月内使用。 In Vivo: 请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方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;体内实验的工作液,建议您现用现配,当天使用;
以下溶剂前显示的百 分比是指该溶剂在您配制终溶液中的体积占比;如在配制过程中出现沉淀、析出现象,可以通过加热和/或超声的方式助溶 1. 请依序添加每种溶剂: 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 2.08 mg/mL (6.08 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (6.08 mM,饱和度未知) 的澄清溶液。 以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀;向上述体系中加入50 μL Tween-80,混合均匀;然后继续加入 450 μL生理盐水定容至 1 mL。 2. 请依序添加每种溶剂: 10% DMSO 90% (20%SBE-β-CDin saline) Solubility: ≥ 2.08 mg/mL (6.08 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (6.08 mM,饱和度未知) 的澄清溶液。 以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中,混合均匀。 3. 请依序添加每种溶剂: 10% DMSO 90%corn oil Solubility: ≥ 2.08 mg/mL (6.08 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (6.08 mM,饱和度未知) 的澄清溶液,此方案不适用于实验周期在半个月以上的实验。 以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中,混合均匀。 *以上所有助溶剂都可在本网站选购。
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