| 规格 | 价格 | 库存 | 数量 |
|---|---|---|---|
| 10 mM * 1 mL in DMSO |
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| 2mg |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| 500mg |
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| Other Sizes |
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| 体外研究 (In Vitro) |
与 JAK2 相比，Pacritinib (SB1518) 对抗 TYK2 的效力是 JAK2 的两倍 (IC50=50 nM)，对抗 JAK3 的效力是 23 倍 (IC50=520 nM)，对抗 JAK1 的效力是 56 倍 (IC50=1280 nM)。当在与其米氏常数 (Km) 相当的三磷酸腺苷浓度下针对 100 nM Pacritinib 进行测试时，其余评估的激酶表现出 <30% 的抑制。 paritinib 抑制 MV4-11 和 MOLM-13 细胞的 IC50 分别为 47 和 67 nM，这些细胞是由 FLT3 ITD 突变引起的人类急性髓性白血病产生的细胞系。 JAK2 信号依赖细胞系 Karpas 1106P 和 Ba/F3-JAK2V617F 被 paritinib 抑制，IC50 值分别为 348 和 160 nM。相应地[1]。用不同剂量的 pacritinib (SB1518) 处理携带 FLT3-ITD 的 MV4-11 细胞 3 小时，并测量 pFLT3、pSTAT5 和 pERK1/2 的量。 pFLT3、pSTAT5、pERK1/2 和 pAkt 均表现出对帕瑞替尼的剂量依赖性降低，IC50 值分别为 80、40、33 和 29 nM。与 MV4-11 和 MOLM-13 细胞中的 FLT3-ITD 相比，RS4;11 中 FLT3-wt 自身磷酸化的 IC50 大四倍 (IC50=600 nM)。然而，在显着较低的 Pacritinib 浓度下观察到 STAT5 抑制 (IC50=8 nM)[2]。
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| 体内研究 (In Vivo) |
在 Ba/F3-JAK2V617F 植入模型中，从细胞接种后 4 天开始，给小鼠每日服用 50 或 150 mg/kg pacritinib (SB1518)，持续 13 天，以评估药物的有效性。当试验结束时，载体对照小鼠出现肝肿大（1.3倍）和脾肿大（约7倍），这与有症状的骨髓纤维化患者的症状相似。当以 150 mg/kg 每日一次给药时，SB1518 疗法可显着减轻所有这些症状，导致脾脏重量正常化 60% (± 9%) 和肝脏重量正常化 92% (± 5%)。它的耐受性也很好，导致体重减轻最小，并且没有血液学毒性，例如贫血或血小板减少症[1]。单次口服10 mg/kg后，pacritinib (SB1518)在大鼠体内表现出较快的吸收（tmax=4 h），峰浓度为114 ng/mL，AUC为599 ng·h/mL，终末半衰期约为6小时。单次口服剂量 3 mg/kg 后，狗快速吸收 pacritinib (SB1518)（tmax=2.0 h），峰值约为 12 ng/mL，AUC 为 53 ng·h/mL，终末半衰期为3.4 小时[3]。
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| 动物实验 |
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| 药代性质 (ADME/PK) |
Absorption, Distribution and Excretion
Following oral administration of 200mg pacritinib twice daily, the mean Cmax and AUC0-12 at steady-state were 8.4 mg/L and 95.6 mg*h/L, respectively. The Tmax is approximately 4-5 hours post-dose. Co-administration with food does not significantly impact the pharmacokinetics of pacritinib. Following oral administration of radiolabeled pacritinib, approximately 87% of the radioactivity was recovered in feces and 6% was recovered in urine. Unchanged parent drug was not present in the feces and accounted for only 0.12% of the radioactivity excreted in the urine. The mean apparent volume of distribution of pacritinib at steady-state is 229 L. The mean apparent clearance of pacritinib is 2.09 L/h. Metabolism / Metabolites Pacritinib metabolism is mediated primarily by CYP3A4. While it undergoes extensive metabolism to at least four identified metabolites - M1, M2, M3, and M4 - parent drug is the major circulating component in plasma and is responsible for the pharmacologic activity. The two major metabolites, M1 and M2, represent 9.6% and 10.5% of parent drug exposure, respectively. Biological Half-Life The mean effective half-life of pacritinib is 27.7 hours. |
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| 毒性/毒理 (Toxicokinetics/TK) |
Hepatotoxicity
In the published preregistration clinical trials of pacritinib, rates of serum ALT elevations were not provided, and no mention of ALT elevations are given in the product label or FDA review of efficacy and safety for its approval. Nevertheless, rates of ALT or AST elevations in several small clinical trials were said to be 15%, with 6% being above 5 times the upper limit of normal (ULN). Since its approval and more widespread clinical use, there have been no reports of serum enzyme or bilirubin elevations or instances of clinically apparent liver injury associated with the use of pacritinib, but it has been clinically available for a short time only. Likelihood score: E* (unproven, but possible cause of clinically apparent liver injury including reactivation of hepatitis B). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the use of pacritinib during breastfeeding. The manufacturer recommends that breastfeeding be withheld during therapy and for 2 weeks after the last dose. An alternate drug is preferred, especially while nursing a newborn or preterm infant. ◉ 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 Pacritinib is 98.8% protein-bound in plasma. |
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| 参考文献 |
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| 其他信息 |
Pharmacodynamics
Pacritinib is administered orally twice daily, with or without food. It should not be used in patients with moderate or severe (Child-Pugh B or C) hepatic impairment, nor in patients with significant renal impairment (eGFR <30 mL/min). Patients taking pacritinib may experience a prolonged QTc interval - while no cases of torsades de pointes have been reported in clinical trials, QTc prolongations to >500 msec and/or increases in baseline QTc by >60 msec were observed in some patients during clinical trials. A baseline QTc interval should be obtained prior to initiating therapy and regular monitoring (including for risk factors, e.g. hypokalemia) should continue throughout therapy. |
| 分子式 |
C28H32N4O3
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|---|---|---|
| 分子量 |
472.58
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| 精确质量 |
472.247
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| CAS号 |
937272-79-2
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| 相关CAS号 |
Pacritinib hydrochloride;1228923-43-0
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| PubChem CID |
46216796
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| 外观&性状 |
Light yellow to yellow solid powder
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| 密度 |
1.2±0.1 g/cm3
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| 沸点 |
711.4±70.0 °C at 760 mmHg
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| 闪点 |
384.0±35.7 °C
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| 蒸汽压 |
0.0±2.3 mmHg at 25°C
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| 折射率 |
1.574
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|
| LogP |
4.23
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| tPSA |
68.74
|
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| 氢键供体(HBD)数目 |
1
|
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| 氢键受体(HBA)数目 |
7
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| 可旋转键数目(RBC) |
4
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| 重原子数目 |
35
|
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| 分子复杂度/Complexity |
644
|
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| 定义原子立体中心数目 |
0
|
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| SMILES |
C1CCN(C1)CCOC2=C3COC/C=C/COCC4=CC(=CC=C4)C5=NC(=NC=C5)NC(=C3)C=C2
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| InChi Key |
HWXVIOGONBBTBY-ONEGZZNKSA-N
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| InChi Code |
InChI=1S/C28H32N4O3/c1-2-13-32(12-1)14-17-35-27-9-8-25-19-24(27)21-34-16-4-3-15-33-20-22-6-5-7-23(18-22)26-10-11-29-28(30-25)31-26/h3-11,18-19H,1-2,12-17,20-21H2,(H,29,30,31)/b4-3+
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| 化学名 |
11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
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| 别名 |
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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 |
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| 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) |
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|---|---|---|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 1 mg/mL (2.12 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 10.0 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: 1 mg/mL (2.12 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。 例如，若需制备1 mL的工作液，可将 100 μL 10.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。 *20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。 View More
配方 3 中的溶解度: ≥ 0.3 mg/mL (0.63 mM) (饱和度未知) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 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 | 2.1160 mL | 10.5802 mL | 21.1604 mL | |
| 5 mM | 0.4232 mL | 2.1160 mL | 4.2321 mL | |
| 10 mM | 0.2116 mL | 1.0580 mL | 2.1160 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 |
| NCT06159491 | Not yet recruiting | Drug: Pacritinib Drug: Azacitidine |
Chronic Myelomonocytic Leukemia |
Douglas Tremblay | January 2, 2024 | Phase 1 Phase 2 |
| NCT02765724 | Completed | Drug: Pacritinib | Myelofibrosis | CTI BioPharma | January 2015 | Phase 1 |
| NCT05552183 | Recruiting | Drug: oral dose of 200 mg pacritinib twice daily (BID) |
Hepatic Impairment | CTI BioPharma | December 12, 2022 | Phase 1 |
| NCT04858256 | Recruiting | Drug: Pacritinib | T-Cell Neoplasm Lymphoproliferative Disorders |
University of Michigan Rogel Cancer Center |
March 29, 2023 | Phase 2 |
Pacritinib effectively blocks FLT3 signaling in FLT3-ITD (MV4-11, MOLM-13) or FLT3-wt (RS;4-11) cells.Blood Cancer J.2011Nov;1(11):e44. |
Pacritinib is efficacious in xenografts derived from cell lines harboring FLT3-ITD.Blood Cancer J.2011Nov;1(11):e44. |
Activated JAK2 signaling in MV4-11 cells after selective inhibition of FLT3 induces FLT3-TKI resistance.Blood Cancer J.2011Nov;1(11):e44. |
Pacritinib induces cell cycle arrest and apoptosis in FLT3-ITD- (MV4-11, MOLM-13) and FLT3-wt- (RS;4-11) harboring cancer cells.Blood Cancer J.2011Nov;1(11):e44. |
Pacritinib inhibits proliferation of AML cells with highest potency in FLT3-ITD harboring cells.Blood Cancer J.2011Nov;1(11):e44. |
Pacritinib blocks proliferation and induces apoptosis inex vivoexpanded primary AML blast cells.Blood Cancer J.2011Nov;1(11):e44. |
JAK3-IN-16
iBFAR2
TyK2-IN-21-d3
JAK2-IN-11
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