Pacritinib
别名: SB1518
Pacritinib是有效的选择性Janus Kinase 2 (JAK2)和Fms-Like Tyrosine Kinase-3 (FLT3)抑制剂，无细胞试验中IC50分别为23和22 nM。Phase 3。
Pacritinib Chemical Structure
CAS: 937272-79-2
产品质控
批次：
纯度：
99.94%
99.94
常与Pacritinib一起在实验中被使用的化合物
Pacritinib和Fedratinib是JAK抑制剂，已被批准用于治疗骨髓纤维化。
Waksal JA, et al. Curr Hematol Malig Rep. 2022 Oct;17(5):140-154.
Pacritinib和Temozolomide的使用显示了BBB渗透并改善了原位异种移植小鼠模型中的总体中位生存期。
Pacritinib和Rapamycin的使用增强了异种GVHD模型和体外对人类T细胞的抑制。
Pidala J, et al. Clin Cancer Res. 2021 May 15;27(10):2712-2722.
Pacritinib可保护人树突状细胞(DC)共刺激分子的分化和上调，而Rruxolitinib会严重损害其分化和功能。
Pacritinib和Pracinostat完全消除JAK2自磷酸化并增强Set-2细胞的细胞死亡。
Novotny-Diermayr V, et al. Blood Cancer J. 2012 May;2(5):e69.
Pacritinib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 |
|---|---|---|---|---|---|
| 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 | ||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | Pacritinib是有效的选择性Janus Kinase 2 (JAK2)和Fms-Like Tyrosine Kinase-3 (FLT3)抑制剂，无细胞试验中IC50分别为23和22 nM。Phase 3。 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 特性 | 双重JAK2/FLT3抑制剂，治疗骨髓纤维化正处于3期临床阶段。 | |||||||||||
| 靶点 |
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| 体外研究(In Vitro) | ||||
| 体外研究活性 | Pacritinib是野生型JAK2和JAK2V617F的抑制剂（IC 50是19 nM），它高频率存在于MPD患者中。相对于JAK2，Pacritinib对TYK2（IC 50是50 nM）的抑制作用低2倍，对JAK3（IC 50是520 nM）的抑制作用低23倍，对JAK1（IC 50是50 nM）的抑制作用低56倍。Pacritinib有效地渗透细胞调节JAK2的下游信号通路，无论是受体激动剂激活或突变型激活。在JAK2WT- and JAK2V617F-缺少细胞中，Pacritinib诱导细胞凋亡，细胞周期阻滞和抗增殖作用。Pacritinib抑制Karpas 1106P and Ba/F3-JAK2V617F细胞增殖，IC 50分别是348 nM和160 nM。Pacritinib从抑制红细胞和髓系祖细胞来源的内在性菌落生长，IC50分别为63 nM和53 nM。[1] SB1518也抑制FLT3基因及突变FLT3-D835Y（IC50是6 nM）。在FLT3基因内部串联重复（ITD），FLT3-野生型细胞和原发性AML原始细胞中，Pacritinib抑制FLT3磷酸化和下游STAT，MAPK和PI3K信号。 在含FLT3-ITD的MV4-11细胞中，Pacritinib剂量依赖性减少pFLT3，pSTAT5，PERK1/ 2和pAKT，IC50分别为80 nM，40 nM，33 nM和29 nM。Pacritinib处理原代AML细胞3小时剂量依赖性的减少pFLT3，pSTAT3和pSTAT5，IC 50低于0.5 μM。在FLT3突变和FLT3-wt细胞中，Pacritinib诱导细胞凋亡，细胞周期停滞和抗增殖作用。Pacritinib抑制含FLT3-ITD的MV4-11细胞和原代AML细胞增殖，IC50分别为47 nM 和0.19-1.3 nM。[2] | |||
|---|---|---|---|---|
| 激酶实验 | 激酶活性检测 | |||
| 所有测定均在384孔白色微量滴定板中进行。化合物4-倍系列稀释8级，从10μM开始。反应混合物由25 μL的测定缓冲液（50 mM HEPES pH值为7.5 ，10mM氯化镁，5 mM氯化锰，1 mM DTT， 0.1 mM的钒酸钠，5 mM的β -甘油磷酸）。对FLT3的测定中，反应含有2.0微克/毫升的FLT3酶，5 μM聚（谷氨酸，酪氨酸）底物和4 μM ATP。对于JAK1测定中，反应含有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。对于JAK2测定中，反应物含有0.35微克/毫升的JAK2酶，10 μM聚（谷氨酸，丙氨酸，酪氨酸），衬底和0.15 μM ATP。对于JAK3测定中，反应物含有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。对TYK2测定中，反应物含有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。反应在加入13 μL PKLight®检测试剂之前在室温温育2小时。温育10分钟之后读取在多标记平板读数器读取发光信号。 | ||||
| 细胞实验 | 细胞系 | Karpas 1106P细胞 | ||
| 浓度 | ~10 μM | |||
| 孵育时间 | 2 天 | |||
| 方法 | 细胞按30〜50％密度接种在96孔板中，并用不同浓度的化合物（一式三份）处理48小时。细胞活力使用CellTiter-格洛测定检测。 | |||
| 实验图片 | 检测方法 | 检测指标 | 实验图片 | 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 | |
| 体内研究(In Vivo) | ||
| 体内研究活性 | Pacritinib(150毫克/千克)口服q.d.到JAK2 V617F相关移植瘤模型中，可显著改善脾肿大和肝的症状，使60％脾脏重量和92％肝脏重量的正常化，无显著体重减轻或任何血液学毒性，包括血小板减少症和贫血。 Pacritinib诱导剂量依赖性的抑制了JAK2V617F依赖性的SET-2异种移植物的生长（75毫克/千克时为40％和150毫克/千克时为61％）。[1] Pacritinib对 FLT3-ITD息MV4-11异种移植模型是有效的。 Pacritinib治疗，每日一次，连续21天，诱导了剂量依赖性的肿瘤生长抑制（25毫克/千克时为38％，50毫克/千克时为92％，100毫克/千克时为121％）。在50和100毫克/公斤/天组分别观察到3/10和8/8只小鼠肿瘤完全消退。[2] | |
|---|---|---|
| 动物实验 | Animal Models | 人巨核细胞白血病移植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 |
化学信息&溶解度
| 分子量 | 472.58 | 分子式 | C28H32N4O3 |
| CAS号 | 937272-79-2 | SDF | Download Pacritinib SDF |
| Smiles | C1CCN(C1)CCOC2=C3COCC=CCOCC4=CC(=CC=C4)C5=NC(=NC=C5)NC(=C3)C=C2 | ||
| 储存条件(自收到货起) | |||
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体外溶解度 |
DMSO : 11 mg/mL ( (23.27 mM) ；DMSO吸湿会降低化合物溶解度，请使用新开封DMSO) Water : Insoluble Ethanol : Insoluble |
摩尔浓度计算器 |
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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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