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Niraparib (MK-4827)
中文名稱：尼拉帕尼
Niraparib (MK4827)是一種口服有效的選擇性PARP-1和PARP-2抑制劑，可在有BRCA和PTEN功能缺陷的臨床腫瘤模型中引起合成致死性。Niraparib 可形成PARP–DNA復(fù)合物并導(dǎo)致DNA損傷、凋亡和細胞死亡。Phase 3。
Niraparib (MK-4827) Chemical Structure
CAS: 1038915-60-4
產(chǎn)品質(zhì)控
批次：
純度：
99.97%
99.97
Niraparib (MK-4827)相關(guān)產(chǎn)品
| 相關(guān)靶點 | PARP1 PARP2 PARP3 Tankyrase-1 Tankyrase-2 PARP14 PARP7 TNKS1 TNKS2 | 點擊展開 |
|---|---|---|
| 相關(guān)產(chǎn)品 | XAV-939 Veliparib (ABT-888) PJ34 HCl AG-14361 Iniparib (BSI-201) A-966492 G007-LK UPF 1069 AZD2461 Pamiparib ME0328 3-Aminobenzamide NMS-P118 Stenoparib (E7449) NVP-TNKS656 WIKI4 Benzamide BGP-15 2HCl NU1025 BYK204165 Fluzoparib (SHR-3162) Picolinamide | 點擊展開 |
| 相關(guān)化合物庫 | FDA藥物庫 天然產(chǎn)物庫 凋亡分子化合物庫 DNA損傷/ DNA修復(fù)化合物庫 細胞周期化合物庫 | 點擊展開 |
相關(guān)信號通路圖
細胞實驗數(shù)據(jù)示例
| 細胞系 | 實驗類型 | 給藥濃度 | 孵育時間 | 活性描述 | 文獻信息 |
|---|---|---|---|---|---|
| Antitumor assay | MDA-MB-436 | 50 mg/kg | 33 days | Antitumor activity against human MDA-MB-436 cells expressing BRCA1 5396 + 1G>A mutant xenografted in CD1 mouse assessed as tumor regression at 50 mg/kg, po bid for 33 days | 19873981 |
| Antitumor assay | MDA-MB-436 | 100 mg/kg | 33 days | Antitumor activity against human MDA-MB-436 cells expressing BRCA1 5396 + 1G>A mutant xenografted in CD1 mouse assessed as tumor regression at 100 mg/kg, po qd for 33 days | 19873981 |
| Antitumor assay | MDA-MB-436 | 80 mg/kg | 1 to 2 weeks | Antitumor activity against human MDA-MB-436 cells harboring BRCA1 mutant xenografted in immunocompromised mouse assessed as tumor growth inhibition at 80 mg/kg, po qd for 1 to 2 weeks | 25761096 |
| Antitumor assay | MDA-MB-436 | 80 mg/kg | 4 weeks | Antitumor activity against human MDA-MB-436 cells harboring BRCA1 mutant xenografted in immunocompromised mouse assessed as complete and sustained tumor regression at 80 mg/kg, po qd for 4 weeks | 25761096 |
| Antitumor assay | MDA-MB-436 | 80 mg/kg | 3 weeks | Antitumor activity against human MDA-MB-436 cells harboring BRCA1 mutant xenografted in immunocompromised mouse assessed as tumor shrinkage at 80 mg/kg, po qd for 3 weeks | 25761096 |
| Antitumor assay | MDA-MB-436 | 50 mg/kg | Antitumor activity against human MDA-MB-436 cells harboring BRCA1 mutant xenografted in immunocompromised mouse assessed as tumor growth inhibition at 50 mg/kg, po administered daily | 25761096 | |
| UWB1.289 cells | Cytotoxicity assay | 5-7 days | Cytotoxicity against human UWB1.289 cells carrying BRCA1 mutant assessed as inhibition of cell proliferation after 5 to 7 days by CellTiter-Blue assay, CC50=0.056 μM | 25761096 | |
| SUM149PT cells | Cytotoxicity assay | 5-7 days | Cytotoxicity against human SUM149PT cells carrying BRCA1 mutant assessed as inhibition of cell proliferation after 5 to 7 days by CellTiter-Blue assay, CC50=0.024 μM | 25761096 | |
| DoTc2-4510 cells | Cytotoxicity assay | 5-7 days | Cytotoxicity against human DoTc2-4510 cells carrying BRCA2 mutant assessed as inhibition of cell proliferation after 5 to 7 days by CellTiter-Blue assay, CC50=0.023 μM | 25761096 | |
| SUM1315MO2 cells | Cytotoxicity assay | 12 days | Cytotoxicity against human SUM1315MO2 cells carrying BRCA1 mutant assessed as inhibition of cell proliferation after 12 days by CellTiter-Blue assay, CC50=0.02 μM | 25761096 | |
| MDA-MB-436 cells | Proliferation assay | 6 days | Antiproliferative activity against human MDA-MB-436 cells expressing BRCA1 5396 + 1G>A mutant after 6 days by cell titer-blue assay, CC50=18 nM | 19873981 | |
| A549 cells | Cytotoxicity assay | 5-7 days | Cytotoxicity against human A549 cells transfected with BRCA2 shRNA assessed as inhibition of cell proliferation after 5 to 7 days by CellTiter-Blue assay, CC50=0.011 μM | 25761096 | |
| BT20 cells | Cytotoxicity assay | 5-7 days | Cytotoxicity against human BT20 cells assessed as inhibition of cell proliferation after 5 to 7 days by CellTiter-Blue assay, CC50=2.2 μM | 25761096 | |
| Antiproliferative assay | HeLa | 7 days | Antiproliferative activity against BRCA1 deficient human HeLa cells after 7 days by cell titer-blue assay, CC50 = 0.033 μM. | 19873981 | |
| Antiproliferative assay | Capan1 | 13 days | Antiproliferative activity against human Capan1 cells expressing BRCA2 6174delT mutation and loss of wild-type allele after 13 days by cell titer-blue assay, CC50 = 0.09 μM. | 19873981 | |
| Antiproliferative assay | HeLa | 7 days | Antiproliferative activity against human HeLa cells expressing wild type BRCA1 after 7 days by cell titer-blue assay, CC50 = 0.86 μM. | 19873981 | |
| Function assay | Jurkat | 96 hrs | Inhibition of PARP1 in human Jurkat cells assessed as reduction of cell viability after 96 hrs by MTS assay, EC50 = 31 μM. | 23850199 | |
| Cytotoxicity assay | HeLa | 5 to 7 days | Cytotoxicity against human HeLa cells transfected with BRCA1 shRNA assessed as reduction of cell viability after 5 to 7 days by CellTiter-Blue assay, CC50 = 0.034 μM. | 25761096 | |
| Cytotoxicity assay | HeLa | 5 to 7 days | Cytotoxicity against wild type human HeLa cells assessed as inhibition of cell proliferation after 5 to 7 days by CellTiter-Blue assay, CC50 = 0.852 μM. | 25761096 | |
| Cytotoxicity assay | UWB1.289 | 5 to 7 days | Cytotoxicity against human UWB1.289 cells expressing BRCA1 assessed as inhibition of cell proliferation after 5 to 7 days by CellTiter-Blue assay, CC50 = 0.975 μM. | 25761096 | |
| Cytotoxicity assay | A549 | 5 to 7 days | Cytotoxicity against wild type human A549 cells assessed as inhibition of cell proliferation after 5 to 7 days by CellTiter-Blue assay, CC50 = 1.76 μM. | 25761096 | |
| Capan1 cells | Cytotoxicity assay | Cytotoxicity against BRCA2-deficient human Capan1 cells, CC50=0.09 μM | 25761096 | ||
| HeLa cells | Function assay | Inhibition of PARP in hydrogen peroxide-induced human HeLa cells assessed as inhibition DNA-damage-induced PARylation, EC50=0.004 μM | 19873981 | ||
| Jurkat cells | Function assay | Inhibition of PARP1 in human Jurkat cells assessed as reduction of cell viability after 96 hrs by MTS assay in presence of 100 uM of temozolomide, EC50=0.2 μM | 23850199 | ||
| Function assay | HeLa | Inhibition of PARP in hydrogen peroxide-induced human HeLa cells assessed as inhibition DNA-damage-induced PARylation, EC90 = 0.045 μM. | 19873981 | ||
| Function assay | CAPAN-1 | Inhibition of PARP in BRCA2-deficient human CAPAN-1 cells assessed as inhibition of hydrogen peroxide-induced PARylation by cell-based assay, IC50 = 0.0035 μM. | 25761096 | ||
| Function assay | HeLa | Inhibition of PARP in human HeLa cells assessed as inhibition of hydrogen peroxide-induced PARylation by cell-based assay, EC50 = 0.004 μM. | 25761096 | ||
| Function assay | A2780 | Inhibition of PARP in human A2780 cells assessed as inhibition of hydrogen peroxide-induced PARylation by cell-based assay, IC50 = 0.004 μM. | 25761096 | ||
| Cytotoxicity assay | MDA-MB-436 | Cytotoxicity against human MDA-MB-436 cells carrying BRCA1 mutant assessed as inhibition of cell proliferation, CC50 = 0.018 μM. | 25761096 | ||
| Function assay | HeLa | Inhibition of PARP in human HeLa cells assessed as inhibition of hydrogen peroxide-induced PARylation by cell-based assay, IC90 = 0.046 μM. | 25761096 | ||
| Function assay | CAPAN-1 | Inhibition of PARP in BRCA2-deficient human CAPAN-1 cells assessed as inhibition of hydrogen peroxide-induced PARylation by cell-based assay, IC90 = 0.05 μM. | 25761096 | ||
| Function assay | A2780 | Inhibition of PARP in human A2780 cells assessed as inhibition of hydrogen peroxide-induced PARylation by cell-based assay, IC90 = 0.052 μM. | 25761096 | ||
| Cytotoxicity assay | Capan1 | Cytotoxicity against BRCA2-deficient human Capan1 cells, EC50 = 0.65 μM. | 26652717 | ||
| qHTS assay | TC32 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells | 29435139 | ||
| qHTS assay | A673 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells | 29435139 | ||
| qHTS assay | NB1643 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells | 29435139 | ||
| qHTS assay | A673 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for A673 cells) | 29435139 | ||
| qHTS assay | BT-37 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-37 cells | 29435139 | ||
| qHTS assay | SK-N-MC | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells | 29435139 | ||
| qHTS assay | NB-EBc1 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells | 29435139 | ||
| qHTS assay | LAN-5 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells | 29435139 | ||
| qHTS assay | SK-N-MC | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-MC cells | 29435139 | ||
| qHTS assay | TC32 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for TC32 cells | 29435139 | ||
| 點擊查看更多細胞系數(shù)據(jù) | |||||
生物活性
| 產(chǎn)品描述 | Niraparib (MK4827)是一種口服有效的選擇性PARP-1和PARP-2抑制劑，可在有BRCA和PTEN功能缺陷的臨床腫瘤模型中引起合成致死性。Niraparib 可形成PARP–DNA復(fù)合物并導(dǎo)致DNA損傷、凋亡和細胞死亡。Phase 3。 | ||||
|---|---|---|---|---|---|
| 靶點 |
|
| 體外研究(In Vitro) | ||||
| 體外研究活性 | 在完整細胞試驗中，MK-4827抑制PARP的活性，EC50為4 nM，并抑制攜帶BRCA-1和BRCA-2突變的癌細胞的增殖，IC50為10-100 nM。它能有效地抑制PARP-1和PARP-2，IC分別為3.8 nM和2.1 nM。它對PARP-3, V-PARP和tankyrase-1的選擇性低100倍以上，IC50分別為1300、330、570 nM。MK-4827能夠抑制攜帶有天然BRCA-1和BRCA-2突變的癌細胞的增殖、通過RNA干擾抑制BRCA-1缺陷的Hela細胞的生長。在攜帶BRCA-1突變的MDA-MB-436人類乳腺腺癌的細胞中，MK-4827的CC50=18 nM；而在BRCA-2缺陷的CAPAN-1人胰腺癌細胞中，CC50=90 nM。而正常人類前列腺和乳腺上皮細胞對MK-4827具有耐藥性，在微摩爾范圍內(nèi)具有抗凋亡作用，說明這些PARP抑制劑在具有BRCA-1和BRCA-2突變的癌細胞中具有選擇性細胞毒性，對周圍組織影響小[2]。 | |||
|---|---|---|---|---|
| 細胞實驗 | 細胞系 | BRCA1基因沉默的Hela細胞 | ||
| 濃度 | 系列稀釋濃度 | |||
| 孵育時間 | 7天 | |||
| 方法 | 將細胞置于96孔黑色viewplates中，細胞密度為300/孔，每孔含190 μLDMEM培養(yǎng)基(含10%胎牛血清，0.1 mg/mL青-鏈霉素雙抗，2 mM L-谷氨酰胺)，在37℃、5% CO2的細胞培養(yǎng)箱中培養(yǎng)4小時。將系列稀釋的抑制劑加入其中，每孔10 μL，使化合物濃度達到工作濃度、DMSO為0.5%。然后在細胞在細胞培養(yǎng)箱中培養(yǎng)7天。7天后，測定細胞活力。 | |||
| 實驗圖片 | 檢測方法 | 檢測指標 | 實驗圖片 | PMID |
| Western blot | c-PARP /c-caspase 3 / γ-H2AX |
|
29158830 | |
| Immunofluorescence | Rad51 / Geminin |
|
27614696 | |
| 體內(nèi)研究(In Vivo) | ||
| 體內(nèi)研究活性 | MK-4827能夠顯著增強輻射對人類腫瘤移植體（p53野生型或p53突變型）的效果[1]。在體內(nèi)實驗中，其耐受良好。單獨使用時，在BRCA-1缺陷型移植瘤模型中具有一定功效[2]。 | |
|---|---|---|
| 動物實驗 | Animal Models | 雌性裸鼠 |
| Dosages | 25 mg/kg每日兩次或50 mg/kg每日一次 | |
| Administration | 口服 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT05289648 | Not yet recruiting | Endometrial Cancer|Serous Adenocarcinoma|Uterine Neoplasm |
Sir Mortimer B. Davis - Jewish General Hospital |
May 1 2024 | Early Phase 1 |
| NCT06077877 | Recruiting | Neoplasms |
GlaxoSmithKline |
October 24 2023 | Phase 1|Phase 2 |
| NCT05666349 | Withdrawn | Recurrent Glioblastoma |
University College London|GlaxoSmithKline |
October 13 2023 | Phase 1 |
化學(xué)信息&溶解度
| 分子量 | 320.39 | 分子式 | C19H20N4O |
| CAS號 | 1038915-60-4 | SDF | Download Niraparib (MK-4827) SDF |
| Smiles | C1CC(CNC1)C2=CC=C(C=C2)N3C=C4C=CC=C(C4=N3)C(=O)N | ||
| 儲存條件(自收到貨起) | |||
|
體外溶解度 |
DMSO : 64 mg/mL ( (199.75 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO) Ethanol : 64 mg/mL (199.75 mM) Water : Insoluble |
摩爾濃度計算器 |
|
體內(nèi)溶解度 現(xiàn)配現(xiàn)用，請按從左到右的順序依次添加，澄清后再加入下一溶劑 |
動物體內(nèi)配方計算器 | ||||
實驗計算
動物體內(nèi)配方計算器（澄清溶液）
第一步：請輸入基本實驗信息（考慮到實驗過程中的損耗，建議多配一只動物的藥量）
mg/kg
g
μL
只
第二步：請輸入動物體內(nèi)配方組成（配方適用于不溶于水的藥物；不同批次藥物配方比例不同，請聯(lián)系Selleck為您提供正確的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
計算結(jié)果：
工作液濃度： mg/ml；
DMSO母液配制方法： mg 藥物溶于μL DMSO溶液（母液濃度mg/mL，注：如該濃度超過該批次藥物DMSO溶解度，請先聯(lián)系Selleck）；
體內(nèi)配方配制方法：取μL DMSO母液，加入μL PEG300，混勻澄清后加入μL Tween 80，混勻澄清后加入μL ddH2O，混勻澄清。
體內(nèi)配方配制方法：取μL DMSO母液，加入μL Corn oil，混勻澄清。
注意：1. 首先保證母液是澄清的；
2.一定要按照順序依次將溶劑加入，進行下一步操作之前必須保證上一步操作得到的是澄清的溶液，可采用渦旋、超聲或水浴加熱等物理方法助溶。
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* 必填項
常見問題及建議解決方法
問題 1:
How to reconstitute the compound for in vivo studies?
回答：
You can use the formulation 1% CMC-Na (suspension) for oral administration.
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