Palbociclib
概述
描述
Palbociclib is a medication developed by Pfizer for the treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative breast cancer . It is a selective inhibitor of cyclin-dependent kinases 4 and 6, which play a crucial role in cell cycle regulation . This compound was the first cyclin-dependent kinase 4 and 6 inhibitor to be approved as a cancer therapy .
作用机制
帕博西尼通过选择性抑制细胞周期蛋白依赖性激酶4和6发挥作用 . 这些激酶参与细胞周期的调节，特别是从G1期向S期的转变 . 通过抑制这些激酶，帕博西尼阻止了视网膜母细胞瘤蛋白的磷酸化，而视网膜母细胞瘤蛋白的磷酸化对于细胞周期进程是必需的 . 这种抑制导致细胞周期在G1期停滞，从而阻止癌细胞增殖 .
与相似化合物的比较
该类别中的其他相似化合物包括利博西尼和阿贝西尼 . 虽然这三种药物都抑制细胞周期蛋白依赖性激酶4和6，但它们在药代动力学和药效学特征方面存在差异 . 例如，阿贝西尼有三种活性代谢物，具有类似的效力，而帕博西尼和利博西尼的代谢物在临床上没有意义 . 此外，阿贝西尼具有明确的暴露-疗效关系，而帕博西尼和利博西尼的这种关系尚无定论 .
生化分析
Biochemical Properties
Palbociclib acts in the cell cycle machinery . It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6 . CDK4 and CDK6 form complexes with cyclin D to promote phosphorylation of the retinoblastoma (Rb) protein, which allows cell cycle progression .
Cellular Effects
This compound inhibits cell viability and blocks cell cycle at the G1 phase, inducing cell senescence . It also inhibits migration and invasion in certain cancer cells . In breast cancer cells, this compound works with hormonal therapy drugs to slow the cancer’s growth and spread .
Molecular Mechanism
This compound is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6 . It blocks the transition from the G1 to the S phase by binding to CDK4/6, inhibiting Rb protein phosphorylation . This prevents the cell from passing the restriction point and exiting G1, thereby halting the cell cycle .
Temporal Effects in Laboratory Settings
This compound has shown significant inhibitory effects in various tumor models in vivo . It has been observed that a short exposure of cells to this compound is sufficient to produce a stable cell-cycle arrest and long-term senescence . After washing out the drug, this compound-treated cells release the drug to the medium, which can induce senescence in susceptible cells .
Dosage Effects in Animal Models
In animal models, this compound has shown significant inhibitory effects on tumor growth at various dosages . The effects of this compound vary with different dosages, with substantial reductions in total tumor volumes and in Ki-67 proliferation marker expression observed .
Metabolic Pathways
This compound is mainly metabolized in the liver via oxidation and sulfonation, primarily by the cytochrome P450 isoenzyme 3A and the sulfotransferase 2A1 . Acylation and glucuronidation are minor metabolic pathways .
Transport and Distribution
This compound concentrates in intracellular acidic vesicles, where it can be readily observed due to its intrinsic fluorescence . It is released from these vesicles upon dilution or washing out of the extracellular medium .
Subcellular Localization
This compound is stored in acidic vesicles within the cell . This lysosomal trapping of this compound explains the prolonged temporal activity of the drug, its paracrine activity, and its cooperation with other lysosomotropic drugs .
准备方法
帕博西尼的制备涉及多种合成路线和反应条件。 一种方法包括以下步骤 :
关环反应： 2-乙酰基-2-丁烯酸甲酯和丙二腈在碱性条件下反应生成1,4,5,6-四氢-2-甲氧基-4-甲基-5-乙酰基-6-氧基-3-吡啶碳腈。
取代反应： 中间产物在酸结合剂的作用下与卤代环戊烷反应生成N-环戊基-1,4,5,6-四氢-2-甲氧基-4-甲基-5-乙酰基-6-氧基-3-吡啶碳腈。
缩合反应： 中间产物与N-[5-(1-哌嗪基)-2-吡啶基]胍反应生成6-乙酰基-8-环戊基-5,8-二氢-5-甲基-2-[5-(1-哌嗪基)-2-吡啶基]氨基-吡啶并[2,3-d]嘧啶-7(6H)-酮。
脱氢反应： 中间产物与硒酸钠反应制备帕博西尼。
化学反应分析
科学研究应用
Breast Cancer
The primary indication for palbociclib is in combination with endocrine therapy for advanced breast cancer. Key clinical trials have demonstrated its efficacy:
- PALOMA-1 Trial : This Phase 2 study showed that the combination of this compound and letrozole significantly prolonged progression-free survival (PFS) in postmenopausal women with estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer. The median PFS was reported at 20.2 months compared to 10.2 months for letrozole alone .
- PALOMA-2 Trial : A Phase 3 trial confirmed these findings, reporting a 44% reduction in the risk of disease progression when this compound was added to letrozole. The trial highlighted an improved median PFS exceeding one year .
Other Cancers
Beyond breast cancer, this compound is being investigated for its potential applications in various malignancies:
- Hepatocellular Carcinoma (HCC) : Preclinical studies indicate that this compound can suppress tumor growth in liver cancer models. It has shown effectiveness in promoting cell cycle arrest and improving survival rates when combined with standard treatments like sorafenib .
- Head and Neck Cancers : Ongoing clinical trials are exploring the use of this compound in treating head and neck squamous cell carcinoma, suggesting a broader application beyond breast cancer .
- Non-Small Cell Lung Cancer (NSCLC) : Research is also underway to evaluate the efficacy of this compound in NSCLC, particularly in cases where traditional therapies have failed .
Case Studies
Several case studies illustrate the real-world applications of this compound:
-
Case Study: ER+ Breast Cancer
A 62-year-old postmenopausal woman with advanced ER+ breast cancer received this compound combined with letrozole after progressing on prior endocrine therapy. The patient achieved a PFS of over 18 months, highlighting the drug's effectiveness even after previous treatments. -
Case Study: Hepatocellular Carcinoma
In a preclinical model, mice treated with this compound alongside sorafenib exhibited a significant reduction in tumor size compared to those receiving sorafenib alone. This suggests that this compound may enhance the efficacy of existing HCC treatments .
Safety and Side Effects
While this compound has shown promising results, it is associated with certain adverse effects, primarily myelosuppression. Clinical trials reported higher rates of neutropenia among patients treated with this compound compared to those receiving placebo or other therapies . Monitoring blood counts is essential during treatment to manage these risks effectively.
相似化合物的比较
Other similar compounds in this class include Ribociclib and Abemaciclib . While all three drugs inhibit cyclin-dependent kinases 4 and 6, they have differences in their pharmacokinetic and pharmacodynamic profiles . For example, Abemaciclib has three active metabolites with similar potency, whereas the metabolites of Palbociclib and Ribociclib are not of clinical significance . Additionally, Abemaciclib has a clear exposure-efficacy relationship, while such relationships for this compound and Ribociclib remain inconclusive .
生物活性
Palbociclib, a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), has emerged as a significant therapeutic agent in the treatment of hormone receptor-positive (HR+) breast cancer. This article provides a comprehensive overview of its biological activity, including detailed research findings, case studies, and data tables.
This compound functions by inhibiting CDK4 and CDK6, which play crucial roles in cell cycle regulation. By blocking these kinases, this compound prevents the phosphorylation of retinoblastoma protein (RB1), leading to cell cycle arrest in the G1 phase. This action is particularly beneficial in HR+ breast cancer, where dysregulation of the cell cycle is common.
In Vitro Studies
Recent studies have demonstrated that this compound effectively reduces phosphorylated RB1 levels in various breast cancer cell lines. For instance, a comparative study showed that treatment with this compound at doses of 100 nM and 500 nM resulted in significant decreases in p-RB1 levels after 72 hours of exposure. The cytotoxic effects were also assessed using senescence-associated β-galactosidase (SA-β-gal) staining, indicating that both this compound and ribociclib induce cellular senescence at higher concentrations .
| Cell Line | Dose (nM) | p-RB1 Reduction | SA-β-gal Staining |
|---|---|---|---|
| T47D | 100 | Moderate | Increased |
| T47D | 500 | Significant | Highest |
| MCF7 | 100 | Moderate | Increased |
| MCF7 | 500 | Significant | Highest |
Gene Expression Changes
Gene expression profiling revealed that this compound significantly alters the expression of genes associated with various PAM50 intrinsic subtypes. Notably, it increased the Luminal A and Normal-like signatures while decreasing Basal-like and HER2-enriched signatures. This suggests that this compound not only inhibits cell proliferation but also modifies tumor biology towards a less aggressive phenotype .
Clinical Efficacy
This compound's clinical efficacy has been substantiated through pivotal trials such as PALOMA-1 and PALOMA-2. In these studies, this compound combined with letrozole demonstrated a marked improvement in progression-free survival (PFS) compared to letrozole alone. Real-world data further support these findings, showing high clinical benefit rates among patients treated with this compound .
Case Studies
A real-world study involving 162 patients treated with this compound plus letrozole reported a 94% six-month PFS rate. The objective response rate (ORR) was noted at 65%, indicating substantial effectiveness in routine clinical practice .
| Treatment Regimen | 6-Month PFS Rate | Objective Response Rate |
|---|---|---|
| This compound + Letrozole | 94% | 65% |
| This compound + Fulvestrant | 95% | Not specified |
Safety Profile
While this compound is generally well-tolerated, side effects such as neutropenia are common. Monitoring hematologic parameters is essential during treatment to manage potential adverse effects effectively.
属性
IUPAC Name |
6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C24H29N7O2/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) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
AHJRHEGDXFFMBM-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC1=C(C(=O)N(C2=NC(=NC=C12)NC3=NC=C(C=C3)N4CCNCC4)C5CCCC5)C(=O)C |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C24H29N7O2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID40972590 |
Source
|
| Record name | Palbociclib | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID40972590 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
447.5 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
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. |
Source
|
| Record name | Palbociclib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09073 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
CAS No. |
571190-30-2 |
Source
|
| Record name | Palbociclib | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=571190-30-2 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Palbociclib [USAN:INN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0571190302 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Palbociclib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09073 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Palbociclib | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID40972590 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | 6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]-8H-pyrido[2,3-d]pyrimidin-7-one | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/information-on-chemicals | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | PALBOCICLIB | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/G9ZF61LE7G | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
Melting Point |
263-266 ºC |
Source
|
| Record name | Palbociclib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09073 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
Synthesis routes and methods
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Retrosynthesis Analysis
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Feasible Synthetic Routes
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