LY2606368
(Synonyms: 5-[[5-[2-(3-氨基丙氧基)-6-甲氧基苯基]-1H-吡唑-3-基]氨基]-2-吡嗪甲腈,LY2606368) 目录号 : GC15663
LY2606368 是一种 ATP 竞争性 CHK1 抑制剂，目前处于临床阶段，Ki 为 0.9 nM，IC50 <1 nM。
Cas No.:1234015-52-1
Sample solution is provided at 25 µL, 10mM.
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LY2606368, an ATP-competitive CHK1 inhibitor, is currently in the clinical stage with a Ki of 0.9 nM and an IC50 of <1 nM. LY2606368 inhibits CHK2 (IC50=8 nM) and RSK1 (IC50=9 nM)[2].
Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe[1].LY2606368 triggered S-phase DNA damage, such as pH2AX (S139) and TUNEL positive staining cells significantly increased in S-phase cells. LY2606368 also requires CDC25A and CDK2 to trigger DNA damage. In addition, LY2606368 causes replication catastrophe[1]. In primary patient-derived osteosarcoma cells, LY2606368 alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double-stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations[3]. To investigate the combined effect of the Chk1 inhibitor LY2606368and antitumor drugs (GEM and S 1) on pancreatic cancer cell line SUIT 2. Acombination of LY2606368 and GS showed effective induction of apoptosis[4]. HGSOC cell lines were also sensitive to LY2606368, associated with induction of DNA damage and replication stress. LY2606368 also sensitized these cell lines to PARP inhibition and compromised both HR repair and replication fork stability[5]. BRCAwt HGSOC develops resistance to LY2606368 monotherapy via a prolonged G2 delay induced by lower CDK1/CyclinB1 activity, thus preventing cells from mitotic catastrophe and cell death[6]. PLK1 or CHEK1 inhibitors (BI-2536 or LY2606368) were found to exert a superior anticancer effect against cell lines at low nanomolar concentrations and induce cell-cycle arrest[7].
Up to 72.3% inhibition of tumor growth was observed in the three doses of LY2606368 tested, and mice lost no more than 3% of their body weight, indicating that LY2606368 was well tolerated in any treatment group. In addition, tumor regrowth was slow in the highest dose group during the 28-day recovery period, indicating a durable tumor response to LY2606368[1].
References:
[1]: King C, Diaz HB,et,al. Barda D, Marshall MS. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Mol Cancer Ther. 2015 Sep;14(9):2004-13. doi: 10.1158/1535-7163.MCT-14-1037. Epub 2015 Jul 3. PMID: 26141948.
[2]: Yin Y, Shen Q, et,al. Chk1 inhibition potentiates the therapeutic efficacy of PARP inhibitor BMN673 in gastric cancer. Am J Cancer Res. 2017 Mar 1;7(3):473-483. PMID: 28401005; PMCID: PMC5385637.
[3]: Heidler CL, Roth EK, et,al. Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient-derived osteosarcoma cells and synergizes with cisplatin and talazoparib. Int J Cancer. 2020 Aug 15;147(4):1059-1070. doi: 10.1002/ijc.32814. Epub 2019 Dec 19. PMID: 31782150; PMCID: PMC7384073.
[4]: Morimoto Y, Takada K, et,al. Prexasertib increases the sensitivity of pancreatic cancer cells to gemcitabine and S?1. Oncol Rep. 2020 Feb;43(2):689-699. doi: 10.3892/or.2019.7421. Epub 2019 Nov 28. PMID: 31789403.
[5]: Parmar K, Kochupurakkal BS, et,al. The CHK1 Inhibitor Prexasertib Exhibits Monotherapy Activity in High-Grade Serous Ovarian Cancer Models and Sensitizes to PARP Inhibition. Clin Cancer Res. 2019 Oct 15;25(20):6127-6140. doi: 10.1158/1078-0432.CCR-19-0448. Epub 2019 Aug 13. PMID: 31409614; PMCID: PMC6801076.
[6]: Nair J, Huang TT, et,al. Resistance to the CHK1 inhibitor prexasertib involves functionally distinct CHK1 activities in BRCA wild-type ovarian cancer. Oncogene. 2020 Aug;39(33):5520-5535. doi: 10.1038/s41388-020-1383-4. Epub 2020 Jul 9. PMID: 32647134; PMCID: PMC7426265.
[7]: Yoshida K, Yokoi A, et,al. Aberrant Activation of Cell-Cycle-Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma. Clin Cancer Res. 2022 May 13;28(10):2147-2159. doi: 10.1158/1078-0432.CCR-22-0100. PMID: 35302600.
LY2606368 是一种 ATP 竞争性 CHK1 抑制剂，目前处于临床阶段，Ki 为 0.9 nM，IC50 <1 nM。 LY2606368 抑制 CHK2 (IC50=8 nM) 和 RSK1 (IC50=9 nM)[2]。
用 LY2606368 处理细胞导致 TUNEL 和 pH2AX- 快速出现S 期细胞群中的阳性双链 DNA 断裂。半胱天冬酶抑制剂 Z-VAD-FMK 对细胞凋亡的抑制对染色体断裂没有影响，表明 LY2606368 导致复制灾难[1]。LY2606368 引发 S 期 DNA 损伤，如 pH2AX (S139) S期细胞中TUNEL阳性染色细胞明显增多。 LY2606368 还需要 CDC25A 和 CDK2 来触发 DNA 损伤。此外，LY2606368 会导致复制灾难[1]。在原发性患者来源的骨肉瘤细胞中，LY2606368 单独导致低纳摩尔浓度下的克隆形成存活率大大降低，并通过影响细胞周期进程、诱导细胞凋亡和诱导双链 DNA 断裂而起作用，浓度远低于临床可耐受和安全的血浆浓度[3]。研究Chk1抑制剂LY2606368和抗肿瘤药物（GEM和S 1）联合作用对胰腺癌细胞系SUIT 2的影响。LY2606368和GS联用显示出有效诱导细胞凋亡[4]。 HGSOC 细胞系也对 LY2606368 敏感，与 DNA 损伤和复制应激的诱导有关。 LY2606368 还使这些细胞系对 PARP 抑制敏感，并损害 HR 修复和复制叉稳定性[5]。 BRCAwt HGSOC 通过较低的 CDK1/CyclinB1 活性诱导的延长的 G2 延迟对 LY2606368 单一疗法产生耐药性，从而防止细胞发生有丝分裂灾难和细胞死亡[6]。 PLK1 或 CHEK1 抑制剂（BI-2536 或 LY2606368）被发现在低纳摩尔浓度下对细胞系发挥优异的抗癌作用，并诱导细胞周期停滞[7]。
在所测试的三个剂量的 LY2606368 中观察到高达 72.3% 的肿瘤生长抑制，小鼠体重减轻不超过 3%，表明 LY2606368 在任何治疗组中都具有良好的耐受性。此外，在 28 天的恢复期内，最高剂量组的肿瘤再生缓慢，表明对 LY2606368[1] 的持久肿瘤反应。
| Kinase experiment [1]: | |
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Preparation Method |
Purified CHK1 was incubated with LY2606368 and substrate was added to detect whether LY2606368 was inhibited. |
|
Reaction Conditions |
10-6-10nM LY2606368 |
|
Applications |
LY2606368 is an ATP-competitive protein kinase inhibitor with a Ki of 0.9 nmol/L against purified CHK1. |
| Cell experiment [2]: | |
|
Cell lines |
HeLa cells |
|
Preparation Method |
Cells were treated with LY2606368 for 7 hours and stained for evidence of DNA DSB using both TUNEL and an antibody for H2AX phosphorylated on serine 139. |
|
Reaction Conditions |
33 nmol/L LY2606368 for 7 hours |
|
Applications |
LY2606368 triggered S-phase DNA damage, such as pH2AX (S139) and TUNEL positive staining cells significantly increased in S-phase cells. LY2606368 also requires CDC25A and CDK2 to trigger DNA damage. In addition, LY2606368 causes replication catastrophe. |
| Animal experiment [3]: | |
|
Animal models |
Female CD-1nu-/nu mice carrying CALU-6 tumors (26-28 g) |
|
Preparation Method |
Vehicle consisting of 20% Captisol (CyDex Inc) pH4 or LY2606368 was administered by subcutaneous injection in a volume of 200 ml(10 mmol/L). 4,8, 12, 24, and 48 hours after drug administration, blood for plasma drug exposure was extracted |
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Dosage form |
1, 3.3, or 10 mg/kg LY2606368 twice daily for 2 days |
|
Applications |
Up to 72.3% inhibition of tumor growth was observed in the three doses of LY2606368 tested, and mice lost no more than 3% of their body weight, indicating that LY2606368 was well tolerated in any treatment group. In addition, tumor regrowth was slow in the highest dose group during the 28-day recovery period, indicating a durable tumor response to LY2606368. |
|
References: [1]. King C, Diaz HB, et,al. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Mol Cancer Ther. 2015 Sep;14(9):2004-13. doi: 10.1158/1535-7163.MCT-14-1037. Epub 2015 Jul 3. PMID: 26141948. |
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| Cas No. | 1234015-52-1 | SDF | |
| 别名 | 5-[[5-[2-(3-氨基丙氧基)-6-甲氧基苯基]-1H-吡唑-3-基]氨基]-2-吡嗪甲腈,LY2606368 | ||
| 化学名 | (Z)-5-((5-(2-(3-aminopropoxy)-6-methoxyphenyl)-1H-pyrazol-3(2H)-ylidene)amino)pyrazine-2-carbonitrile | ||
| 分子式 | C18H19N7O2 | 分子量 | 365.39 |
| 溶解度 | <0.73mg/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。 |
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| 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 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.7368 mL | 13.684 mL | 27.368 mL |
| 5 mM | 0.5474 mL | 2.7368 mL | 5.4736 mL |
| 10 mM | 0.2737 mL | 1.3684 mL | 2.7368 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: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet