Prexasertib dimesylate (LY2606368 dimesylate) 是一种选择性的，ATP 竞争性的第二代细胞周期检测点激酶 1 (CHK1) 抑制剂，Ki为 0.9 nM，IC50为<1 nm。prexasertib dimesylate 抑制 CHK2 (IC50=8 nM) 和 RSK1 (IC50=9 nM)。Prexasertib dimesylate 引起双链 DNA 断裂和复制突变，导致细胞凋亡 (apoptosis)。Prexasertib dimesylate 显示有效的抗肿瘤活性。
| 生物活性 | Prexasertib dimesylate (LY2606368 dimesylate) is a selective, ATP-competitive second-generationcheckpoint kinase 1 (CHK1)inhibitor with aKiof 0.9 nM and anIC50of<1 nm. prexasertib dimesylate inhibitsCHK2(IC50=8 nM) andRSK1(IC50=9 nM). Prexasertib dimesylate causes double-stranded DNA breakage and replication catastrophe resulting inapoptosis. Prexasertib dimesylate shows potent anti-tumor activity[1][2]. |
| IC50& Target[1] | Chk1 0.9 nM (Ki) | Chk1 <1 nM (IC50) | Chk2 8 nM (IC50) |
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体外研究
(In Vitro) | Prexasertib dimesylate (LY2606368 dimesylate) inhibits MELK (IC50=38 nM), SIK (IC50=42 nM), BRSK2 (IC50=48 nM), ARK5 (IC50=64 nM). Prexasertib dimesylate requires CDC25A and CDK2 to cause DNA damage[1].
Prexasertib dimesylate (33, 100 nM; for 7 hours) results in DNA damage during S-phase in HeLa cells[1].
Prexasertib dimesylate (8-250 nM; pre-treated for 15 minutes) inhibits CHK1 autophosphorylation (S296) and CHK2 autophosphorylation (S516) in HT-29 cells[1].
Prexasertib dimesylate (4 nM; 24 hours) results in a large shift in cell-cycle populations from G1 and G2-M to S-phase with an accompanied induction of H2AX phosphorylation in U-2 OS cells[1].
Prexasertib dimesylate (33 nM; for 12 hours) causes chromosomal fragmentation in HeLa cells. Prexasertib dimesylate (100 nM; 0.5 to 9 hours) induces replication stress and depletes the pool of available RPA2 for binding to DNA[1].
Cell Cycle Analysis[1] | Cell Line: | HeLa cells | | Concentration: | 33, 100 nM | | Incubation Time: | For 7 hours | | Result: | Had an IC50of 37 nM and resulted in the G2-M population received DNA damage during S-phase but continued to progress through the cell cycle into an early mitosis. |
Western Blot Analysis[1] | Cell Line: | HT-29 cells | | Concentration: | 8, 16, 31, 63, 125, 250 nM | | Incubation Time: | Pre-treated for 15 minutes | | Result: | Inhibited CHK1 autophosphorylation (S296) and CHK2 autophosphorylation (S516) (IC50of less than 31 nM) in HT-29 cells. |
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体内研究
(In Vivo) | Prexasertib dimesylate (LY2606368 dimesylate; 1-10 mg/kg; SC; twice daily for 3 days, rest 4 days; for three cycles) causes growth inhibition in tumor xenografts[1].
Prexasertib dimesylate (15 mg/kg; SC) causes CHK1 inhibition in the blood and the phosphorylation of both H2AX (S139) and RPA2 (S4/S8)[1].
| Animal Model: | Female CD-1 nu-/nu- mice (26-28 g) with Calu-6 cells[1] | | Dosage: | 1, 3.3, or 10 mg/kg | | Administration: | SC; twice daily for 3 days, rest 4 days; for three cycles | | Result: | Caused statistically significant tumor growth inhibition (up to 72.3%). |
| Animal Model: | Female CD-1 nu-/nu- mice (26-28 g) with Calu-6 cells[1] | | Dosage: | 15 mg/kg (Pharmacokinetic Analysis) | | Administration: | SC (200 μL) | | Result: | CHK1 was 7 ng/mL at 12 hours and 3 ng/mL by 24 hours in plasma exposures.
Phosphorylation of both H2AX (S139) and RPA2 (S4/S8) was detectable at 4 hours, showing the rapid occurrence of DNA damage. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | 4°C, stored under nitrogen *In solvent : -80°C, 6 months; -20°C, 1 month (stored under nitrogen) |
| 溶解性数据 | In Vitro: DMSO : 100 mg/mL(179.34 mM;Need ultrasonic) H2O : 50 mg/mL(89.67 mM;Need ultrasonic) 配制储备液 | 1 mM | 1.7934 mL | 8.9670 mL | 17.9340 mL | | 5 mM | 0.3587 mL | 1.7934 mL | 3.5868 mL | | 10 mM | 0.1793 mL | 0.8967 mL | 1.7934 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 (stored under nitrogen)。-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: ≥ 3.5 mg/mL (6.28 mM); Clear solution
此方案可获得 ≥ 3.5 mg/mL (6.28 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 35.0 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: ≥ 3.5 mg/mL (6.28 mM); Clear solution
此方案可获得 ≥ 3.5 mg/mL (6.28 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 35.0 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。 *以上所有助溶剂都可在本网站选购。
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