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Pacritinib
別名: SB1518
Pacritinib是有效的選擇性Janus Kinase 2 (JAK2)和Fms-Like Tyrosine Kinase-3 (FLT3)抑制劑，無細胞試驗中IC50分別為23和22 nM。Phase 3。
Pacritinib Chemical Structure
CAS: 937272-79-2
產(chǎn)品質(zhì)控
批次：
純度：
99.94%
99.94
常與Pacritinib一起在實驗中被使用的化合物
Pacritinib和Fedratinib是JAK抑制劑，已被批準用于治療骨髓纖維化。
Waksal JA, et al. Curr Hematol Malig Rep. 2022 Oct;17(5):140-154.
Pacritinib和Temozolomide的使用顯示了BBB滲透并改善了原位異種移植小鼠模型中的總體中位生存期。
Pacritinib和Rapamycin的使用增強了異種GVHD模型和體外對人類T細胞的抑制。
Pidala J, et al. Clin Cancer Res. 2021 May 15;27(10):2712-2722.
Pacritinib可保護人樹突狀細胞(DC)共刺激分子的分化和上調(diào)，而Rruxolitinib會嚴重損害其分化和功能。
Pacritinib和Pracinostat完全消除JAK2自磷酸化并增強Set-2細胞的細胞死亡。
Novotny-Diermayr V, et al. Blood Cancer J. 2012 May;2(5):e69.
Pacritinib相關產(chǎn)品
相關信號通路圖
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 |
|---|---|---|---|---|---|
| KMS-12-BM | Function assay | 2 uM | 3 hrs | Inhibition of JAK2 in IL-6-stimulated human KMS-12-BM cells assessed as suppression of STAT3 phosphorylation at TY705 residue at 2 uM pretreated for 3 hrs followed by IL-6 stimulation by immunoblot method | 27541357 |
| MOLM14 | Function assay | 0.1 uM | 3 hrs | Inhibition of JAK2 in IL-6-stimulated human MOLM14 cells assessed as suppression of STAT3 phosphorylation at TY705 residue at 0.1 uM pretreated for 3 hrs followed by IL-6 stimulation by immunoblot method | 27541357 |
| TAMH | Cytotoxicity assay | 24 hrs | Cytotoxicity against TAMH cells assessed as cell viability after 24 hrs by CellTiter-Glo assay, IC50 = 3.68 μM. | 28953386 | |
| AC10 | Cytotoxicity assay | 24 hrs | Cytotoxicity against human AC10 cells assessed as cell viability after 24 hrs by CellTiter-Glo assay, IC50 = 2.02 μM. | 28953386 | |
| NKYS | Antiproliferative assay | 48 hrs | Antiproliferative activity against human NKYS cells after 48 hrs by CellTiter-Glo luminescent assay, IC50 = 1.6 μM. | 28953386 | |
| KG1 | Antiproliferative assay | 48 hrs | Antiproliferative activity against human KG1 cells after 48 hrs by CellTiter-Glo luminescent assay, IC50 = 1.48 μM. | 28953386 | |
| KHYG | Antiproliferative assay | 48 hrs | Antiproliferative activity against human KHYG cells after 48 hrs by CellTiter-Glo luminescent assay, IC50 = 1.24 μM. | 28953386 | |
| OPM2 | Antiproliferative assay | 48 hrs | Antiproliferative activity against human OPM2 cells after 48 hrs by CellTiter-Glo luminescent assay, IC50 = 1.21 μM. | 28953386 | |
| HEL 92.1.7 | Antiproliferative assay | 36 hrs | Antiproliferative activity against human HEL 92.1.7 cells after 36 hrs by PrestoBlue dye based assay, IC50 = 1.17 μM. | 28953386 | |
| KMS-12-BM | Antiproliferative assay | 48 hrs | Antiproliferative activity against human KMS-12-BM cells after 48 hrs by CellTiter-Glo luminescent assay, IC50 = 0.75 μM. | 28953386 | |
| MOLM14 | Antiproliferative assay | 48 hrs | Antiproliferative activity against human MOLM14 cells after 48 hrs by CellTiter-Glo luminescent assay, IC50 = 0.079 μM. | 28953386 | |
| TAMH | Antiproliferative assay | 24 hrs | Antiproliferative activity against mouse TAMH cells after 24 hrs by CellTiter-Glo assay, IC50 = 3.68 μM. | 27541357 | |
| PC3 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human PC3 cells after 72 hrs by MTT assay, IC50 = 2.41 μM. | 27541357 | |
| MDA-MB-231 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human MDA-MB-231 cells after 72 hrs by MTT assay, IC50 = 2.43 μM. | 27541357 | |
| HEL 92.1.7 | Antiproliferative assay | 48 hrs | Antiproliferative activity against HEL 92.1.7 cells harboring JAK2 V617F mutant after 48 hrs by CellTiter-Glo assay, IC50 = 1.726 μM. | 27541357 | |
| HCT116 | Antiproliferative assay | 48 hrs | Antiproliferative activity against human HCT116 cells after 48 hrs by CellTiter-Glo assay, IC50 = 1.69 μM. | 27541357 | |
| NKYS | Antiproliferative assay | 48 hrs | Antiproliferative activity against human NKYS cells after 48 hrs by CellTiter-Glo assay, IC50 = 1.6 μM. | 27541357 | |
| KG1 | Antiproliferative assay | 48 hrs | Antiproliferative activity against human KG1 cells after 48 hrs by CellTiter-Glo assay, IC50 = 1.48 μM. | 27541357 | |
| KHYG | Antiproliferative assay | 48 hrs | Antiproliferative activity against human KHYG cells after 48 hrs by CellTiter-Glo assay, IC50 = 1.24 μM. | 27541357 | |
| OPM2 | Antiproliferative assay | 48 hrs | Antiproliferative activity against human OPM2 cells after 48 hrs by CellTiter-Glo assay, IC50 = 1.21 μM. | 27541357 | |
| HEL 92.1.7 | Antiproliferative assay | 36 hrs | Antiproliferative activity against HEL 92.1.7 cells harboring JAK2 V617F mutant after 36 hrs by PrestoBlue dye based assay, IC50 = 1.17 μM. | 27541357 | |
| HCT116 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human HCT116 cells after 72 hrs by MTT assay, IC50 = 0.88 μM. | 27541357 | |
| MCF7 | Antiproliferative assay | 48 hrs | Antiproliferative activity against human MCF7 cells after 48 hrs by CellTiter-Glo assay, IC50 = 0.85 μM. | 27541357 | |
| Jurkat | Antiproliferative assay | 48 hrs | Antiproliferative activity against human Jurkat cells after 48 hrs by CellTiter-Glo assay, IC50 = 0.839 μM. | 27541357 | |
| PC3 | Antiproliferative assay | 48 hrs | Antiproliferative activity against human PC3 cells after 48 hrs by CellTiter-Glo assay, IC50 = 0.77 μM. | 27541357 | |
| KMS-12-BM | Antiproliferative assay | 48 hrs | Antiproliferative activity against human KMS-12-BM cells after 48 hrs by CellTiter-Glo assay, IC50 = 0.75 μM. | 27541357 | |
| MCF7 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human MCF7 cells after 72 hrs by MTT assay, IC50 = 0.29 μM. | 27541357 | |
| HL60 | Antiproliferative assay | 48 hrs | Antiproliferative activity against human HL60 cells after 48 hrs by CellTiter-Glo assay, IC50 = 0.52 μM. | 27541357 | |
| MOLM14 | Antiproliferative assay | 48 hrs | Antiproliferative activity against human MOLM14 cells harboring FLT3-ITD mutant after 48 hrs by CellTiter-Glo assay, IC50 = 0.079 μM. | 27541357 | |
| HEL 92.1.7 | Function assay | 1 hr | Induction of JAK2 V617F mutant phosphorylation at Y1007/8 residues in HEL 92.1.7 cells after 1 hr by immunoblot method | 27541357 | |
| HL60 | Antiproliferative assay | Antiproliferative activity against human HL60 cells, IC50 = 1.78 μM. | 28953386 | ||
| Jurkat | Antiproliferative assay | Antiproliferative activity against human Jurkat cells, IC50 = 1.09 μM. | 28953386 | ||
| HL60 | Antiproliferative assay | Antiproliferative activity against human HL60 cells, IC50 = 1.78 μM. | 27541357 | ||
| Jurkat | Antiproliferative assay | Antiproliferative activity against human Jurkat cells, IC50 = 1.09 μM. | 27541357 | ||
| 點擊查看更多細胞系數(shù)據(jù) | |||||
生物活性
| 產(chǎn)品描述 | Pacritinib是有效的選擇性Janus Kinase 2 (JAK2)和Fms-Like Tyrosine Kinase-3 (FLT3)抑制劑，無細胞試驗中IC50分別為23和22 nM。Phase 3。 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 特性 | 雙重JAK2/FLT3抑制劑，治療骨髓纖維化正處于3期臨床階段。 | |||||||||||
| 靶點 |
|
| 體外研究(In Vitro) | ||||
| 體外研究活性 | Pacritinib是野生型JAK2和JAK2V617F的抑制劑（IC 50是19 nM），它高頻率存在于MPD患者中。相對于JAK2，Pacritinib對TYK2（IC 50是50 nM）的抑制作用低2倍，對JAK3（IC 50是520 nM）的抑制作用低23倍，對JAK1（IC 50是50 nM）的抑制作用低56倍。Pacritinib有效地滲透細胞調(diào)節(jié)JAK2的下游信號通路，無論是受體激動劑激活或突變型激活。在JAK2WT- and JAK2V617F-缺少細胞中，Pacritinib誘導細胞凋亡，細胞周期阻滯和抗增殖作用。Pacritinib抑制Karpas 1106P and Ba/F3-JAK2V617F細胞增殖，IC 50分別是348 nM和160 nM。Pacritinib從抑制紅細胞和髓系祖細胞來源的內(nèi)在性菌落生長，IC50分別為63 nM和53 nM。[1] SB1518也抑制FLT3基因及突變FLT3-D835Y（IC50是6 nM）。在FLT3基因內(nèi)部串聯(lián)重復（ITD），F(xiàn)LT3-野生型細胞和原發(fā)性AML原始細胞中，Pacritinib抑制FLT3磷酸化和下游STAT，MAPK和PI3K信號。 在含F(xiàn)LT3-ITD的MV4-11細胞中，Pacritinib劑量依賴性減少pFLT3，pSTAT5，PERK1/ 2和pAKT，IC50分別為80 nM，40 nM，33 nM和29 nM。Pacritinib處理原代AML細胞3小時劑量依賴性的減少pFLT3，pSTAT3和pSTAT5，IC 50低于0.5 μM。在FLT3突變和FLT3-wt細胞中，Pacritinib誘導細胞凋亡，細胞周期停滯和抗增殖作用。Pacritinib抑制含F(xiàn)LT3-ITD的MV4-11細胞和原代AML細胞增殖，IC50分別為47 nM 和0.19-1.3 nM。[2] | |||
|---|---|---|---|---|
| 激酶實驗 | 激酶活性檢測 | |||
| 所有測定均在384孔白色微量滴定板中進行?；衔?-倍系列稀釋8級，從10μM開始。反應混合物由25 μL的測定緩沖液（50 mM HEPES pH值為7.5 ，10mM氯化鎂，5 mM氯化錳，1 mM DTT， 0.1 mM的釩酸鈉，5 mM的β -甘油磷酸）。對FLT3的測定中，反應含有2.0微克/毫升的FLT3酶，5 μM聚（谷氨酸，酪氨酸）底物和4 μM ATP。對于JAK1測定中，反應含有2.5微克/毫升JAK1酶，10μM聚（谷氨酸，丙氨酸，酪氨酸）底物和1.0 μM ATP。對于JAK2測定中，反應物含有0.35微克/毫升的JAK2酶，10 μM聚（谷氨酸，丙氨酸，酪氨酸），襯底和0.15 μM ATP。對于JAK3測定中，反應物含有3.5微克/毫升的JAK3酶，10μM聚（谷氨酸，丙氨酸，酪氨酸）底物和6.0 μM的ATP。對TYK2測定中，反應物含有2.5微克/毫升的TYK2酶，10μM聚（谷氨酸，丙氨酸，酪氨酸）底物和0.15 μM ATP。反應在加入13 μL PKLight?檢測試劑之前在室溫溫育2小時。溫育10分鐘之后讀取在多標記平板讀數(shù)器讀取發(fā)光信號。 | ||||
| 細胞實驗 | 細胞系 | Karpas 1106P細胞 | ||
| 濃度 | ~10 μM | |||
| 孵育時間 | 2 天 | |||
| 方法 | 細胞按30?50％密度接種在96孔板中，并用不同濃度的化合物（一式三份）處理48小時。細胞活力使用CellTiter-格洛測定檢測。 | |||
| 實驗圖片 | 檢測方法 | 檢測指標 | 實驗圖片 | PMID |
| Western blot | pFLT3 / FLT3 / pSTAT5 / STAT5 / GAPDH p-STAT3Y705 / STAT3 / ACTIN / PARP pSTAT3 Y705 / STAT3 / β-Tubulin pSTAT3 Y705 / STAT3 / Actin / MAPK / p-AKT S473 / AKT pFLT3(Y591) / pSTAT5(Y694) / pERK1、2 / pAkt(T308) / β-Actin pFLT3(Y591) / pSTAT5(Y694) / pERK1、2 / pAkt(T308) / β-Actin |
|
31102119 | |
| Growth inhibition assay | Cell viability |
|
29235481 | |
| IHC | HE staining of liver sections HE staining of skin grafts p-STAT3 / Ki-67 / mCD31 / VEGF-A / Bcl-2 |
|
29785143 | |
| Immunofluorescence | Phalloidin TUNEL |
|
27334834 | |
| 體內(nèi)研究(In Vivo) | ||
| 體內(nèi)研究活性 | Pacritinib(150毫克/千克)口服q.d.到JAK2 V617F相關移植瘤模型中，可顯著改善脾腫大和肝的癥狀，使60％脾臟重量和92％肝臟重量的正常化，無顯著體重減輕或任何血液學毒性，包括血小板減少癥和貧血。 Pacritinib誘導劑量依賴性的抑制了JAK2V617F依賴性的SET-2異種移植物的生長（75毫克/千克時為40％和150毫克/千克時為61％）。[1] Pacritinib對 FLT3-ITD息MV4-11異種移植模型是有效的。 Pacritinib治療，每日一次，連續(xù)21天，誘導了劑量依賴性的腫瘤生長抑制（25毫克/千克時為38％，50毫克/千克時為92％，100毫克/千克時為121％）。在50和100毫克/公斤/天組分別觀察到3/10和8/8只小鼠腫瘤完全消退。[2] | |
|---|---|---|
| 動物實驗 | Animal Models | 人巨核細胞白血病移植SET-2 |
| Dosages | 150 mg/kg | |
| Administration | 口服灌胃 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT06303193 | Not yet recruiting | Myelodysplastic Syndromes |
National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) |
May 15 2024 | Phase 1|Phase 2 |
| NCT06052618 | Not yet recruiting | KSHV Inflammatory Cytokine Syndrome (KICS)|Kaposi Sarcoma Herpesvirus -Associated Multicentric Castleman Disease |
National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) |
May 15 2024 | Phase 2 |
| NCT06159491 | Not yet recruiting | Chronic Myelomonocytic Leukemia |
Douglas Tremblay|Sobi Inc.|Icahn School of Medicine at Mount Sinai |
January 2 2024 | Phase 1|Phase 2 |
| NCT05531786 | Recruiting | Graft vs Host Disease |
National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) |
March 6 2023 | Phase 1|Phase 2 |
化學信息&溶解度
| 分子量 | 472.58 | 分子式 | C28H32N4O3 |
| CAS號 | 937272-79-2 | SDF | Download Pacritinib SDF |
| Smiles | C1CCN(C1)CCOC2=C3COCC=CCOCC4=CC(=CC=C4)C5=NC(=NC=C5)NC(=C3)C=C2 | ||
| 儲存條件(自收到貨起) | |||
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體外溶解度 |
DMSO : 11 mg/mL ( (23.27 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO) Water : Insoluble Ethanol : 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。
技術支持
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