Dinaciclib
别名: SCH727965, PS-095760
Dinaciclib是一种新型有效的CDK抑制剂，作用于CDK2，CDK5，CDK1和CDK9，无细胞试验中IC50分别为1 nM，1 nM，3 nM和4 nM。它也会阻断胸甘(dThd) DNA整合。Dinaciclib 可通过激活caspases 8和caspases 9来诱导细胞凋亡。Phase 3。
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Dinaciclib Chemical Structure
CAS: 779353-01-4
产品质控
批次：
纯度：
99.99%
99.99
常与Dinaciclib一起在实验中被使用的化合物
Dinaciclib和Gemcitabine联用比单独使用任何一种治疗方法对肿瘤细胞生长产生更强大和持续的抑制。
Dinaciclib和Cisplatin联合使用会降低细胞活力，并使Ishikawa和HEC-1A细胞对Cisplatin治疗敏感。
Dinaciclib和MK-2206 2HCl组合使用可显着阻止原位Panc265/Panc253模型中的肿瘤生长并显着减少转移灶的数量。
在小鼠中，Dinaciclib和SCH772984的组合使用比单独使用任何一种治疗方法都能更显着地减少肿瘤生长。
Dinaciclib和Vemurafenib在BRAF V600E突变黑色素瘤细胞系A2058/M14中表现出协同抗肿瘤作用。
Dinaciclib相关产品
相关信号通路图
细胞实验数据示例
| 细胞系 | 实验类型 | 给药浓度 | 孵育时间 | 活性描述 | 文献信息 |
|---|---|---|---|---|---|
| WM1366 | Growth Inhibition Assay | 10/30 nM | 72 h | inhibits cell growth and survival | 23527225 |
| 1205Lu | Growth Inhibition Assay | 10/30 nM | 72 h | inhibits cell growth and survival | 23527225 |
| U937 | Function Assay | 2/10 nM | 3 h | blocks induction of XBP-1s and downstream targets | 24362465 |
| BaF3/Bcr-abl | Function Assay | 1.5/3/8 nM | 6 h | blocks induction of XBP-1s and downstream targets | 24362465 |
| K562 | Function Assay | 1.5/3/8 nM | 6 h | blocks induction of XBP-1s and downstream targets | 24362465 |
| H929 | Function Assay | 2/5/10 nM | 4 h | blocks induction of XBP-1s and downstream targets | 24362465 |
| 8226 | Function Assay | 2/5/10 nM | 4 h | blocks induction of XBP-1s and downstream targets | 24362465 |
| U937 | Function Assay | 2/5/10 nM | 3 h | blocks induction of XBP-1s and downstream targets | 24362465 |
| Kasumi-1 | Apoptosis Assay | 100 nM | 24 h | induces cell cycle arrest | 25289887 |
| CA46 | Apoptosis Assay | 100 nM | 24 h | induces cell cycle arrest | 25289887 |
| ML-1 | Apoptosis Assay | 1-1000 nM | 4 h | induces apoptosis slightly | 21768777 |
| Function assay | NCI-H929 | 0.005 uM | 24 hrs | Inhibition of CDK2-mediated Rb phosphorylation at Ser 807/811 in human NCI-H929 cells at 0.005 uM after 24 hrs by immunoblotting analysis | 23600925 |
| Function assay | A673 | 0.05 uM | 24 hrs | Inhibition of CDK2-mediated Rb phosphorylation at Ser 807/811 in human A673 cells at 0.05 uM after 24 hrs by immunoblotting analysis | 23600925 |
| Apoptosis assay | MEC1 | 0.01 uM | 24 hrs | Induction of apoptosis in human MEC1 cells assessed as decrease in MCL-1 level at 0.01 uM after 24 hrs by immunoblotting analysis | 30253346 |
| Apoptosis assay | HL60 | 0.01 uM | 24 hrs | Induction of apoptosis in human HL60 cells assessed as decrease in MCL-1 level at 0.01 uM after 24 hrs by immunoblotting analysis | 30253346 |
| Apoptosis assay | MV4-11 | 0.01 uM | 24 hrs | Induction of apoptosis in human MV4-11 cells assessed as decrease in c-MYC level at 0.01 uM after 24 hrs by immunoblotting analysis | 30253346 |
| Apoptosis assay | MEC1 | 0.01 uM | 24 hrs | Induction of apoptosis in human MEC1 cells assessed as decrease in c-MYC level at 0.01 uM after 24 hrs by immunoblotting analysis | 30253346 |
| Apoptosis assay | MV4-11 | 0.01 uM | 24 hrs | Induction of apoptosis in human MV4-11 cells assessed as decrease in MCL-1 level at 0.01 uM after 24 hrs by immunoblotting analysis | 30253346 |
| Apoptosis assay | HL60 | 0.01 uM | 24 hrs | Induction of apoptosis in human HL60 cells assessed as decrease in c-MYC level at 0.01 uM after 24 hrs by immunoblotting analysis | 30253346 |
| Function assay | Sf9 | 10 uM | IC50 = 0.004 μM | 29329658 | |
| MIAPaCa-2 | Growth Inhibition Assay | 72 h | GI50=10 nM | 21768779 | |
| Pa20C | Growth Inhibition Assay | 72 h | GI50=20 nM | 21768779 | |
| Cytotoxicity assay | MDA-MB-436 | 72 hrs | IC50 = 0.005 μM | 23600925 | |
| Cytotoxicity assay | NCI-H929 | 72 hrs | IC50 = 0.005 μM | 23600925 | |
| Cytotoxicity assay | MDA-MB-231 | 72 hrs | IC50 = 0.005 μM | 23600925 | |
| Cytotoxicity assay | SK-ES-1 | 72 hrs | IC50 = 0.005 μM | 23600925 | |
| Cytotoxicity assay | A673 | 72 hrs | IC50 = 0.005 μM | 23600925 | |
| Cytotoxicity assay | SK-BR-3 | 72 hrs | IC50 = 0.005 μM | 23600925 | |
| Cytotoxicity assay | MNNG-HOS | 72 hrs | IC50 = 0.0055 μM | 23600925 | |
| Cytotoxicity assay | SK-UT-1 | 72 hrs | IC50 = 0.006 μM | 23600925 | |
| Cytotoxicity assay | U266 | 72 hrs | IC50 = 0.006 μM | 23600925 | |
| Cytotoxicity assay | RPMI18226 | 72 hrs | IC50 = 0.009 μM | 23600925 | |
| Cytotoxicity assay | SW872 | 72 hrs | IC50 = 0.0095 μM | 23600925 | |
| Cytotoxicity assay | T47D | 72 hrs | IC50 = 0.01 μM | 23600925 | |
| Apoptosis assay | A673 | 24 hrs | EC50 = 0.011 μM | 23600925 | |
| Cytotoxicity assay | MCF7 | 72 hrs | IC50 = 0.02 μM | 23600925 | |
| Function assay | Sf9 | 1 hr | IC50 = 0.001 μM | 27171036 | |
| Function assay | Sf9 | 1 hr | IC50 = 0.001 μM | 27171036 | |
| Function assay | Sf9 | 1 hr | IC50 = 0.001 μM | 27171036 | |
| Function assay | Sf9 | 1 hr | IC50 = 0.001 μM | 27171036 | |
| Function assay | Sf9 | 1 hr | IC50 = 0.003 μM | 27171036 | |
| Function assay | Sf9 | 1 hr | IC50 = 0.003 μM | 27171036 | |
| Function assay | Sf9 | 1 hr | IC50 = 0.004 μM | 27171036 | |
| Function assay | Sf9 | 1 hr | IC50 = 0.004 μM | 27171036 | |
| Function assay | Sf9 | 1 hr | IC50 = 0.001 μM | 29853338 | |
| Function assay | Sf9 | 1 hr | IC50 = 0.001 μM | 29853338 | |
| Function assay | Sf9 | 1 hr | IC50 = 0.003 μM | 29853338 | |
| Function assay | Sf9 | 1 hr | IC50 = 0.004 μM | 29853338 | |
| Antiproliferative assay | MOLM13 | 72 hrs | GI50 = 0.0033 μM | 30253346 | |
| Antiproliferative assay | MEC1 | 72 hrs | GI50 = 0.0036 μM | 30253346 | |
| Antiproliferative assay | MOLM14 | 72 hrs | GI50 = 0.0045 μM | 30253346 | |
| Antiproliferative assay | COLO205 | 72 hrs | GI50 = 0.0068 μM | 30253346 | |
| Antiproliferative assay | HL60 | 72 hrs | GI50 = 0.008 μM | 30253346 | |
| Antiproliferative assay | Ramos | 72 hrs | GI50 = 0.0086 μM | 30253346 | |
| Antiproliferative assay | GISTT1 | 72 hrs | GI50 = 0.0088 μM | 30253346 | |
| Antiproliferative assay | U937 | 72 hrs | GI50 = 0.01 μM | 30253346 | |
| Antiproliferative assay | A431 | 72 hrs | GI50 = 0.011 μM | 30253346 | |
| Antiproliferative assay | SKM1 | 72 hrs | GI50 = 0.011 μM | 30253346 | |
| Antiproliferative assay | MEC2 | 72 hrs | GI50 = 0.011 μM | 30253346 | |
| Antiproliferative assay | A375 | 72 hrs | GI50 = 0.011 μM | 30253346 | |
| Antiproliferative assay | OCI-AML3 | 72 hrs | GI50 = 0.013 μM | 30253346 | |
| Antiproliferative assay | BE(2)-M17 | 72 hrs | GI50 = 0.021 μM | 30253346 | |
| Antiproliferative assay | CHO | 72 hrs | GI50 = 0.16 μM | 30253346 | |
| Cytotoxicity assay | U2OS | 96 hrs | IC50 = 0.006 μM | ChEMBL | |
| Function assay | U2OS | 1 hr | IC50 = 0.007 μM | ChEMBL | |
| TC-71 | Growth Inhibition Assay | IC50=3.9 nM | 22315240 | ||
| CHLA-266 | Growth Inhibition Assay | IC50=7.3 nM | 22315240 | ||
| BT-12 | Growth Inhibition Assay | IC50=8.5 nM | 22315240 | ||
| Rh30 | Growth Inhibition Assay | IC50=9 nM | 22315240 | ||
| Rh18 | Growth Inhibition Assay | IC50=10.5 nM | 22315240 | ||
| Rh41 | Growth Inhibition Assay | IC50=10.5 nM | 22315240 | ||
| RD | Growth Inhibition Assay | IC50=8.2 nM | 22315240 | ||
| CHLA-9 | Growth Inhibition Assay | IC50=8 nM | 22315240 | ||
| CHLA-10 | Growth Inhibition Assay | IC50=6.3 nM | 22315240 | ||
| CHLA-258 | Growth Inhibition Assay | IC50=9.9 nM | 22315240 | ||
| GBM2 | Growth Inhibition Assay | IC50=6.5 nM | 22315240 | ||
| NB-1643 | Growth Inhibition Assay | IC50=3.3 nM | 22315240 | ||
| NB-EBc1 | Growth Inhibition Assay | IC50=7 nM | 22315240 | ||
| CHLA-90 | Growth Inhibition Assay | IC50=7.5 nM | 22315240 | ||
| CHLA-136 | Growth Inhibition Assay | IC50=9.8 nM | 22315240 | ||
| NALM-6 | Growth Inhibition Assay | IC50=4.6 nM | 22315240 | ||
| COG-LL-317 | Growth Inhibition Assay | IC50=6.5 nM | 22315240 | ||
| RS4;11 | Growth Inhibition Assay | IC50=5.1 nM | 22315240 | ||
| MOLT-4 | Growth Inhibition Assay | IC50=9.3 nM | 22315240 | ||
| CCRF-CEM | Growth Inhibition Assay | IC50=5.6 nM | 22315240 | ||
| Kasumi-1 | Growth Inhibition Assay | IC50=4.5 nM | 22315240 | ||
| Karpas-299 | Growth Inhibition Assay | IC50=3.9 nM | 22315240 | ||
| Ramos-RA1 | Growth Inhibition Assay | IC50=7.9 nM | 22315240 | ||
| Function assay | Sf9 | IC50 = 0.072 μM | 26741853 | ||
| Function assay | sf9 | IC50 = 0.002 μM | 26851505 | ||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | Dinaciclib是一种新型有效的CDK抑制剂，作用于CDK2，CDK5，CDK1和CDK9，无细胞试验中IC50分别为1 nM，1 nM，3 nM和4 nM。它也会阻断胸甘(dThd) DNA整合。Dinaciclib 可通过激活caspases 8和caspases 9来诱导细胞凋亡。Phase 3。 | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 特性 | [1] | ||||||||
| 靶点 |
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| 体外研究(In Vitro) | ||||
| 体外研究活性 | Dinaciclib抑制CDK1和CDK9 效果差不多，但是抑制CDK2和CDK5效果则分别强12和14倍。Dinaciclib作用于A2780细胞，有效抑制的DNA复制，抑制胸甘(dThd)DNA摄入,IC50为4 nM。Dinaciclib 浓度大于6.25 nM时，强抑制Rb在Ser 807/811位点磷酸化。Rb磷酸化的完全抑制与凋亡发生相关，通过用浓度大于6.25 nM 的Dinaciclib处理的细胞中p85 PARP裂解产物的出现来表示。 Dinaciclib有效作用于广谱人肿瘤细胞系。[1] 在羟基脲处理期间加入Dinaciclib,也抑制γ-H2AX累积,这种作用存在剂量依赖性。[2] Dinaciclib 抑制恶性黑色素瘤细胞增殖,使恶性黑色素瘤细胞发生大规模凋亡。[3]Dinaciclib诱导一些骨肉瘤 细胞系凋亡，包括抗Doxorubicin的细胞。Dinaciclib 降低RNAP II 在 serine 2位点磷酸化，也降低CDK抑制剂p27Kip1在threonine 187位点磷酸化。加入12 nM 到40 nM Dinaciclib处理4小时或16小时，最易使磷酸化作用降低。Dinaciclib也降低Rb在serine 807/811位点磷酸化。Dinaciclib诱导mock-和p53-耗尽的U2OS细胞凋亡，凋亡程度相似。 [4] |
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|---|---|---|---|---|
| 激酶实验 | Cyclin/CDK激酶实验 | |||
| 设计从Sf9细胞中纯化的重组cyclin/CDK 全酶，产生表达特定cyclin 或CDK的杆状病毒。 在含 50 mM Tris-HCl (pH 8.0), 10 mM MgCl2, 1 mM DTT,和 0.1 mM原钒酸钠的反应buffer中，Cyclin/CDK 复合体稀释成终浓度为 50 μg/mL。每种激酶反应中, 1 μg酶和 20 μL 2-μM 底物溶液 (组蛋白 H1衍生的一种生物素化的肽段) 混合，然后与10 μL 稀释的Dinaciclib结合。加入 50 μL 2 μM ATP和 0.1 μCi 33P-ATP反应开始。激酶反应在室温下进行1小时，然后加入 0.1% Triton X-100, 1 mM ATP, 5 mM EDTA, 和5 mg/mL 链霉亲和素包被的SPA 磁珠而终止反应。使用96-孔GF/B过滤板和Filtermate广谱收集器 收集SPA 磁珠。用 2 M NaCl 冲洗磁珠两遍，然后用含磷酸的2 M NaCl 再冲洗两遍。使用TopCount 96孔液体闪烁计数器测定信号。 | ||||
| 细胞实验 | 细胞系 | A2780细胞 | ||
| 浓度 | 0 μM-5 μM | |||
| 孵育时间 | 24小时 | |||
| 方法 | A2780 细胞培养在含10%FBS的DMEM培养基上，每周移动两次，通过使用胰蛋白酶-EDTA分离单细胞层。在96孔Cytostar-T板上每孔加入 100 μL A2780细胞 (5 ×103个)，然后在37oC下温育16到24小时。Dinaciclib 在含2% 14C标记 dThd的完全培养基上连续稀释。培养基从 Cytostar T板上转移，按一式四份加入200 μL 多种Dinaciclib 稀释液，然后细胞在37oC下温育24小时。使用闪烁亲近法测定，在TopCoun上测量累积的放射性标记物渗透率。 |
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| 实验图片 | 检测方法 | 检测指标 | 实验图片 | PMID |
| Western blot | Mcl-1 / Bcl-2 / Bcl-xl / Bax / Bak / PUMA / Noxa Cleaved PARP / c-Myc Survivin RNAP II (P-Ser2/P-Ser5) |
|
28714472 | |
| Growth inhibition assay | Cell viability Cell viability |
|
27378523 | |
| Immunofluorescence | cyclin B1 / α-tubulin / Aurora A OCT4 |
|
28207834 | |
| 体内研究(In Vivo) | ||
| 体内研究活性 | Dinaciclib 每天按8, 16, 32,和48 mg/kg 剂量腹腔注射处理 ，持续10天，导致肿瘤受抑制分别为70%, 70%, 89%,和 96%。Dinaciclib MED(最低有效剂量)约为小于8 mg/kg。Dinaciclib耐药性良好, 且最高剂量处理组中体重损失最高为5%。Dinaciclib 在体内具有抗癌活性，存在剂量依赖性，按低于MTD(最高耐受剂量)的剂量水平处理，几乎完全抑制肿瘤生长。Dinaciclib作用于小鼠，具有短暂的血浆半衰期。[1] |
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|---|---|---|
| 动物实验 | Animal Models | 携带A2780肿瘤的裸鼠 |
| Dosages | 8 mg/kg, 16 mg/kg, 32 mg/kg,和 48 mg/kg | |
| Administration | 腹腔注射 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT03484520 | Terminated | Cancer - Acute Myeloid Leukemia |
AbbVie|Merck Sharp & Dohme LLC |
July 23 2018 | Phase 1 |
| NCT01434316 | Active not recruiting | Advanced Malignant Solid Neoplasm |
National Cancer Institute (NCI) |
November 1 2011 | Phase 1 |
化学信息&溶解度
| 分子量 | 396.49 | 分子式 | C21H28N6O2 |
| CAS号 | 779353-01-4 | SDF | Download Dinaciclib SDF |
| Smiles | CCC1=C2N=C(C=C(N2N=C1)NCC3=C[N+](=CC=C3)[O-])N4CCCCC4CCO | ||
| 储存条件(自收到货起) | |||
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体外溶解度 |
DMSO : 79 mg/mL ( (199.24 mM) ；DMSO吸湿会降低化合物溶解度，请使用新开封DMSO) Ethanol : 35 mg/mL (88.27 mM) Water : Insoluble |
摩尔浓度计算器 |
|
体内溶解度 现配现用，请按从左到右的顺序依次添加，澄清后再加入下一溶剂 |
动物体内配方计算器 | ||||
实验计算
动物体内配方计算器（澄清溶液）
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）
mg/kg
g
μL
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Selleck为您提供正确的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
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，注：如该浓度超过该批次药物DMSO溶解度，请先联系Selleck）；
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 ddH2O，混匀澄清。
体内配方配制方法：取μL DMSO母液，加入μL Corn oil，混匀澄清。
注意：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。
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常见问题及建议解决方法
问题 1:
I want to know how to reconstitute the inhibitor for in vivo studies?
回答：
S2768 (SCH727965) in 15% Captisol at 8 mg/ml is a suspension for oral administration. And it can be dissolved in 2% DMSO/30% PEG 300/ddH2O at 10 mg/ml as a clear solution for injection.
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