规格 | 价格 | 库存 | 数量 |
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100mg |
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Other Sizes |
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靶点 |
DYRK1A 2000 nM (IC50) MAPK 8000 nM (IC50) Cdk4/cyclin D3 9 nM (IC50) Cdk4/cyclin D1 11 nM (IC50) Cdk6/cyclin D2 16 nM (IC50)
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体外研究 (In Vitro) |
Palbociclib 盐酸盐(0–1 μM,24 小时)的 IC50 值为 0.063 μM,可抑制 MDA-MB-435 细胞中视网膜母细胞瘤 Ser795 的磷酸化。它还对结肠癌 Colo-205 中的 Ser780 和 Ser795 磷酸化具有类似的影响[1]。仅 G1 期的 MDA-MB-453 细胞会被盐酸哌柏西利(0–10 μM,24 小时)抑制[1]。在 MDA-MB-453 和 MDA-MB-361 细胞中,盐酸哌柏西利(500 nM,7 天)可增强同源基因(H2d1、H2k1 和 B2m)的表达[2]。盐酸哌柏西利(0-1 μM,6 天)的 IC50 值范围为 4 nM 至 1 μM,可抑制许多管腔 ER 阳性和 HER2 扩增乳腺癌细胞系的发育[3]。 Palbociclib 盐酸盐(0-1 μM,3 天)产生可逆的细胞周期停滞并抑制人肝癌细胞系的生长,IC50 值范围为 0.01 μM 至 3.49 μM[4]。
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体内研究 (In Vivo) |
Palbociclib 盐酸盐每天口服 75 或 150 mg/kg,持续 14 天,会导致肿瘤发展更慢并迅速消退[1]。口服盐酸哌柏西利(90 mg/kg,每天 12 天)治疗脾脏和淋巴结中 Treg 计数和 Treg:CD8 比率降低的无肿瘤小鼠,表明与肿瘤无关的作用[2]。 Palbociclib 盐酸盐(口服给药,100 mg/kg,每天一次,持续 1 周)在基因改变肝癌的嵌合小鼠模型中表现出强大的抗肿瘤作用[4]。
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酶活实验 |
CDK 测定在 96 孔滤板中进行,用于动力学分析和 IC50 计算。通过用杆状病毒感染昆虫细胞,所有 CDK-细胞周期蛋白激酶复合物都得到表达和纯化。与 GST 融合的 pRb 的一部分(氨基酸 792-928)用作测定的底物 (GST•RB-Cterm)。 20 mM Tris-HCl,pH 7.4,50 mM NaCl,1 mM 二硫苏糖醇,10 mM MgCl2,25 μM ATP(用于 CDK4-细胞周期蛋白 D1、CDK6-细胞周期蛋白 D2 和 CDK6-细胞周期蛋白 D3)、0.25 μCi [γ-32P ]ATP、20 ng 酶、1 μg GST•RB-Cterm 和适当稀释的抑制剂包含在 0.1 mL 的总反应体积中。将除 [γ-32P]ATP 之外的所有成分添加到孔中后,将它们放在平板混合器上两分钟。添加 [γ-32P]ATP 启动反应,然后在 25°C 下孵育 15 分钟。为了使底物沉淀,通过添加 0.1 mL 20% 三氯乙酸并将板在 4°C 下保持至少 1 小时来终止反应。用 0.2 mL 10% 三氯乙酸洗五次孔后,使用 β 板计数器测量放射性掺入。
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细胞实验 |
细胞增殖检测[3]
细胞类型: ER 阳性以及 HER2 扩增的乳腺癌细胞系(MDA-MB-175、ZR-75-30、CAMA-1 等) .) 测试浓度: 0-1 μM 孵育时间: 6 天 实验结果: 抑制生长Luminal ER 阳性以及 HER2 扩增的乳腺癌细胞系。 细胞周期分析sup>[1] 细胞类型: MDA-MB-453 细胞 测试浓度: 0-1 μM 孵育时间:24小时 实验结果:G1期的MDA-MB-453细胞被抑制。 |
动物实验 |
Animal/Disease Models: Mice bearing Colo-205 colon carcinoma xenografts (p16 deleted)[1]
Doses: 75, 150 mg/kg Route of Administration: Oral administration; daily for 14 days Experimental Results: Produced rapid tumor regressions and a corresponding tumor growth delay of ~50 days. Animal/Disease Models: Tumor-free female FVB mice[2] Doses: 90 mg/kg Route of Administration: Oral administration; daily for 12 days Experimental Results: diminished total thymic mass and immature CD4+ and CD8+ double-positive thymocytes, and increased the fractions of CD4+ and CD8+ single-positive thymocytes. Animal/Disease Models: Genetically engineered mosaic mouse model of liver cancer (Myc;p53 -sgRNA)[4] Doses: 100 mg/kg Route of Administration: Oral administration; daily for 1 week Experimental Results: diminished the luminescence signal in liver and delayed tumor growth. |
药代性质 (ADME/PK) |
Absorption, Distribution and Excretion
Palbociclib presents a linear pharmacokinetic profile and its peak plasma concentration was observed 6-12 hours after oral administration. The oral bioavailability is reported to be of 46% with a steady-state reached after 8 days and a median accumulation ratio of 2.4. The absorption of palbociclib is significantly reduced under fasting conditions and hence, food intake is recommended when this drug is administered. The main route of elimination of palbociclib is through feces after hepatic metabolism while renal clearance seems to play a minor role accounting only for 17.5% of the eliminated dose. The mean apparent distribution of palbociclib is 2583 L which suggests that palbociclib penetrates extensively into peripheral tissues. The mean apparent oral clearance of palbociclib is of 63.1 L/h. Metabolism / Metabolites Palbociclib is mainly hepatically transformed. the metabolism is mainly performed by the activities of the cytochrome P450 isoenzyme 3A and the sulfotransferase 2A1. The metabolism of palbociclib is represented mainly by reactions of oxidation and sulfonation followed by acylation and glucuronidation as minor reactions. After its metabolism, palbociclib forms mainly inactive glucuronide and sulfamic acid conjugates. The major circulating metabolite, accounting for 1.5% of the dose in excreta is is the glucuronide conjugate. Biological Half-Life The mean plasma elimination half-life of palbociclib is 29 hours. |
毒性/毒理 (Toxicokinetics/TK) |
Hepatotoxicity
In the large clinical trials, adverse events were common and led to dose reductions in one-third of patients and discontinuation in 8%. Publications on the efficacy and safety of palbociclib rarely mentioned serum ALT elevations or hepatotoxicity. In a study of women with refractory, metastatic breast cancer, serum ALT elevations occurred in 6% [2% over 5 times ULN] receiving palbociclib and fulvestrant compared to 3% [none over 5 times ULN] on fulvestrant alone. Since its approval and more widescale use, there have been several reports of prominent ALT elevations arising after 2 or 3 cycles of palbociclib, that improved on discontinuation and recurred rapidly when restarted. Serum bilirubin and alkaline phosphatase levels were normal and symptoms were not mentioned. In addition, there have been rare reports of patients with refractory metastatic breast cancer who developed pseudocirrhosis within 2 to 3 months of starting palbociclib presenting with fatigue, jaundice and ascites with only modest elevations in serum aminotransferase and alkaline phosphatase levels. Imaging revealed a severely nodular liver, but liver histology showed desmoplastic changes in areas of necrotic metastatic tumor without cirrhosis. The liver also had vascular changes suggestive of sinusoidal obstruction syndrome, changes possibly caused by the dramatic involution of the metastatic tumor tissue combined with vascular damage. Pseudocirrhosis has been reported with other highly successful antineoplastic therapies of cancer metastatic to the liver, but the frequency is rare. Likelihood score: C (probable rare cause of clinically apparent liver injury that may represent pseudocirrhosis from nodular transformation of the liver in response to necrosis of hepatic metastases). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of palbociclib during breastfeeding. Because palbociclib is 85% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 29 hours and it might accumulate in the infant. It is also given in combination with letrozole or fulvestrant, which may increase the risk to the infant. The manufacturer recommends that breastfeeding be discontinued during palbociclib therapy and for 3 weeks after the last dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Binding of palbociclib to human plasma proteins in vitro accounts for approximately 85% of the administered dose. |
参考文献 | |
其他信息 |
Palbociclib is a member of the class of pyridopyrimidines that is 2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7-one bearing additional methyl, acetyl and cyclopentyl substituents at positions 5, 6 and 8 respectively. It is used in combination with letrozole for the treatment of metastatic breast cancer. It has a role as an EC 2.7.11.22 (cyclin-dependent kinase) inhibitor and an antineoplastic agent. It is a pyridopyrimidine, an aminopyridine, a secondary amino compound, a member of piperidines, an aromatic ketone, a member of cyclopentanes and a tertiary amino compound.
Palbociclib is a piperazine pyridopyrimidine that acts in the cell cycle machinery. It is a second generation cyclin-dependent kinase inhibitor selected from a group of pyridopyrimidine compounds due to its favorable physical and pharmaceutical properties. Palbociclib was developed by Pfizer Inc after the discovery that identified the cyclin-dependent kinases as key regulators of cell growth. It was originally FDA approved on March 2015 for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer and its indications were updated in April 2019 to include male patients based on findings from postmarketing reports and electronic health records demonstrating safety and clinical efficacy. Palbociclib is a Kinase Inhibitor. The mechanism of action of palbociclib is as a Kinase Inhibitor, and Cytochrome P450 3A Inhibitor. Palbociclib is a unique cyclin-dependent kinase inhibitor that is used in combination with aromatase inhibitors in the treatment of postmenopausal women with metastatic breast cancer. Palbociclib is associated with transient and usually mild elevations in serum aminotransferase during therapy and to an unusual form of liver injury called pseudocirrhosis caused by shrinkage of tumor metastases in the liver combined with desmoplastic changes and vascular damage, that can be severe, progressive and even fatal. Palbociclib is an orally available cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic activity. Palbociclib selectively inhibits cyclin-dependent kinase 4 (CDK4) and 6 (CDK6), thereby inhibiting retinoblastoma (Rb) protein phosphorylation early in the G1 phase leading to cell cycle arrest. This suppresses DNA replication and decreases tumor cell proliferation. CDK4 and 6 are serine/threonine kinases that are upregulated in many tumor cell types and play a key role in the regulation of cell cycle progression. See also: Palbociclib Isethionate (is active moiety of). Drug Indication Palbociclib is indicated in combination with [letrozole] as initial endocrine-based therapy for the treatment of human epidermal growth factor receptor type 2 (HER2)-negative and hormone receptor(HR)-positive tumors in adult patients with advanced/metastatic breast cancer. It is as well approved in combination with [fulvestrant] in patients with disease progression with prior endocrine therapy. In the official labeling, the use of palbociclib should be accompanied with either an aromatase inhibition, no restricted to letrozole, as initial endocrine-based therapy in postmenopausal women or in man. The breast cancer starts as a group of cancer cells that grow into and destroy the nearby breast tissue. This growth can spread into other parts of the body which is called metastasis. According to the location of the cancer cells, it can be categorized in ductal carcinoma and lobular carcinoma. However, other types of breast cancer include inflammatory breast cancer, Paget disease of the breast, triple negative breast cancer non-Hodgkin lymphoma and soft tissue sarcoma. In males, breast cancer is usually treated as the cases of postmenopausal women and almost all the cases are ductal carcinoma. FDA Label Ibrance is indicated for the treatment of hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer : in combination with an aromatase inhibitor; in combination with fulvestrant in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone releasing hormone (LHRH) agonist. Treatment of Ewing sarcoma Treatment of breast malignant neoplasms Mechanism of Action Palbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor that acts by binding to the ATP pocket with an IC50 in the range of 9-15 nmol/L. It is important to consider that it presents low to absent activity against other kinases. The CDK4/6 kinase is involved, with coregulatory partner cyclin D, in the G1-S transition. Hence, inhibition of this step prevents cell cycle progression in cells in whose this pathway is functioning. This step includes the pathways of the phosphorylation of retinoblastoma protein and the E2F family of transcription factors. |
分子式 |
C24H30CLN7O2
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分子量 |
514.99
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精确质量 |
519.192
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CAS号 |
571189-11-2
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相关CAS号 |
Palbociclib;571190-30-2;Palbociclib monohydrochloride;827022-32-2;Palbociclib-d8;1628752-83-9;Palbociclib dihydrochloride;Palbociclib orotate;2757498-64-7
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PubChem CID |
60167560
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外观&性状 |
Light yellow to yellow solid powder
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LogP |
5.036
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tPSA |
105.04
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氢键供体(HBD)数目 |
4
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氢键受体(HBA)数目 |
8
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可旋转键数目(RBC) |
5
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重原子数目 |
35
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分子复杂度/Complexity |
775
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定义原子立体中心数目 |
0
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InChi Key |
YORIVNBSTFKZTO-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C24H29N7O2.2ClH/c1-15-19-14-27-24(28-20-8-7-18(13-26-20)30-11-9-25-10-12-30)29-22(19)31(17-5-3-4-6-17)23(33)21(15)16(2)32;;/h7-8,13-14,17,25H,3-6,9-12H2,1-2H3,(H,26,27,28,29);2*1H
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化学名 |
6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one;dihydrochloride
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别名 |
Palbociclib 2HCl; 571189-11-2; PD 0332991 hydrochloride; 6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride; PD-0332991 hydrochloride; 1831842-69-3; 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one;dihydrochloride; PALBOCICLIB DIHYDROCHLORIDE;
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HS Tariff Code |
2934.99.9001
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存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month 注意: 请将本产品存放在密封且受保护的环境中,避免吸湿/受潮。 |
运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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溶解度 (体外实验) |
H2O : 2 mg/mL (3.88 mM)
DMSO : 1.25 mg/mL (2.43 mM) |
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溶解度 (体内实验) |
注意: 如下所列的是一些常用的体内动物实验溶解配方,主要用于溶解难溶或不溶于水的产品(水溶度<1 mg/mL)。 建议您先取少量样品进行尝试,如该配方可行,再根据实验需求增加样品量。
注射用配方
注射用配方1: DMSO : Tween 80: Saline = 10 : 5 : 85 (如: 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)(IP/IV/IM/SC等) *生理盐水/Saline的制备:将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中,得到澄清溶液。 注射用配方 2: DMSO : PEG300 :Tween 80 : Saline = 10 : 40 : 5 : 45 (如: 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline) 注射用配方 3: DMSO : Corn oil = 10 : 90 (如: 100 μL DMSO → 900 μL Corn oil) 示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液,加到 900 μL Corn oil/玉米油中, 混合均匀。 View More
注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如:100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)] 口服配方
口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠) 口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素) 示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中,得到0.5%CMC-Na澄清溶液;然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中,得到悬浮液。 View More
口服配方 3: 溶解于 PEG400 (聚乙二醇400) 请根据您的实验动物和给药方式选择适当的溶解配方/方案: 1、请先配制澄清的储备液(如:用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液,按从左到右的顺序依次添加助溶剂,澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明,并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀/澄清;向上述体系中加入50 μL Tween-80,混合均匀/澄清;然后继续加入450 μL ddH2O (或 saline)定容至 1 mL; 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出,可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果,工作液请现配现用! 6、如不确定怎么将母液配置成体内动物实验的工作液,请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
制备储备液 | 1 mg | 5 mg | 10 mg | |
1 mM | 1.9418 mL | 9.7089 mL | 19.4179 mL | |
5 mM | 0.3884 mL | 1.9418 mL | 3.8836 mL | |
10 mM | 0.1942 mL | 0.9709 mL | 1.9418 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液):对于大多数产品,InvivoChem推荐用DMSO配置母液 (比如:5、10、20mM或者10、20、50 mg/mL浓度),个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息,或者很难将产品溶解在溶液中,请联系我们;
3、建议使用下列计算器进行相关计算(摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等);
4、母液配好之后,将其分装到常规用量,并储存在-20°C或-80°C,尽量减少反复冻融循环。
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)。如该浓度超过该批次药物DMSO溶解度,请首先与我们联系。
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。
(1) 请确保溶液澄清之后,再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶;
(2) 一定要按顺序加入溶剂 (助溶剂) 。
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT03936270 | Active Recruiting |
Drug: Palbociclib 125mg Drug: Letrozole 2.5mg |
Ovarian Cancer | Latin American Cooperative Oncology Group |
January 27, 2020 | Phase 2 |
NCT04288089 | Active Recruiting |
Drug: Palbociclib (75, 100, 125 milligram [mg]) Drug: H3B-6545 (150, 300, 450 mg) |
Receptors, Estrogen Genes, Erbb-2 |
Eisai Inc. | April 1, 2020 | Phase 1 |
NCT02738866 | Active Recruiting |
Drug: Palbociclib Drug: Fulvestrant |
Metastatic Breast Cancer | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins |
October 25, 2016 | Phase 2 |
NCT01864746 | Active Recruiting |
Drug: Palbociclib PD-0332991 Drug: Placebo |
Breast Cancer Her2-normal |
German Breast Group | November 2013 | Phase 3 |
NCT03446157 | Active Recruiting |
Drug: Cetuximab Drug: Palbociclib |
Colonic Cancer Colon Cancer |
UNC Lineberger Comprehensive Cancer Center |
March 13, 2018 | Phase 2 |