Plinabulin (NPI-2358)   中文名称: 普那布林

β-tubulin; microtubule

PlinabuLin (NPI-2358) 是一种有效的抗肿瘤药物，可在多重耐药 (MDR) 肿瘤细胞系中快速诱导微管蛋白解聚和单层通透性。在 HUVEC 中，DU 145 细胞的 IC50 值为 18 nM，PC-3 细胞为 13 nM，MDA-MB-231 细胞为 14 nM，NCI-H292 细胞为 18 nM，Jurkat 白血病细胞为 11 nM。纳米[1]。

当给予普那布林（0 mg/kg–15 mg/kg；腹膜内注射）时，雌性 CDF1 和 C3H/He 小鼠的肿瘤灌注以剂量和时间依赖性方式减少。普那布林的抗癌作用对 KHT 肉瘤比对 C3H 肿瘤更敏感，并且两种模型均表现出增强的放射反应 [3]。

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38名患者入组。根据恶心、呕吐、疲劳、发热、肿瘤疼痛和短暂性血压升高等不良事件，选择30mg /m²的剂量作为RP2D， DCE-MRI显示肿瘤血流量（Ktrans）从13.5 mg/m²（定义生物有效剂量）减少，在30mg /m²评估的患者中减少16%至82%。半衰期为6.06±3.03小时，清除率为30.50±22.88 L/h，分布容积为211±67.9 L。 结论：在RP2D为30 mg/m²时，plinabulin显示出良好的安全性，同时通过减少肿瘤血流量、肿瘤疼痛和其他机械相关不良事件来引发生物学效应。在这些结果的基础上，开始了普萘布林联合标准化疗药物的额外临床试验。[2]

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普林布林（7.5 mg/kg）在注射后1小时内显著降低初始曲线下面积（IAUC）和传递常数（K（反式）），在3小时内达到最低点，但在24小时内恢复正常。IAUC和K（反式）在3小时内呈剂量依赖性下降。在C3H肿瘤中，直到12.5 mg/kg的剂量达到，才观察到显著的抗肿瘤作用，但在KHT肉瘤中，从1.5 mg/kg开始。在注射plinabulin后1小时照射肿瘤可增强两种模型的反应。 结论：普那布林诱导肿瘤灌注降低具有时间和剂量依赖性。KHT肉瘤比C3H肿瘤对普林布林的抗肿瘤作用更敏感，两种模型的放射反应均增强。[3]

Diketopiperazine NPI-2358是NPI-2350的合成类似物，NPI-2350是从Aspergillus sp.中分离出来的天然产物，它能解聚A549人肺癌细胞中的微管。虽然在结构上不同于目前报道的秋水仙碱结合位点药物，但NPI-2358可以结合微管蛋白的秋水仙碱结合位点。NPI-2358对多种人类肿瘤细胞系具有有效的体外抗肿瘤活性，并保持对多种多重耐药（MDR）肿瘤细胞系的活性。此外，当在增殖的人脐静脉内皮细胞（HUVECs）中进行评估时，浓度低至10 nmol/l的NPI-2358可在30分钟内诱导微管蛋白解聚。此外，NPI-2358剂量依赖性地增加HUVEC单层通透性——肿瘤血管塌陷的体外模型。NPI-2358与秋水仙碱、长春新碱和康布他汀A-4 （CA4）三种具有血管破坏活性的微管蛋白解聚剂进行了比较。结果表明，NPI-2358在HUVECs中的活性高于秋水仙碱和长春新碱；CA4的谱线与NPI-2358的谱线接近。综上所述，我们的数据表明NPI-2358是一种有效的抗肿瘤药物，在MDR肿瘤细胞系中具有活性，并且能够快速诱导huvec中的微管蛋白解聚和单层通透性。这些数据为进一步评估NPI-2358作为体内血管破坏剂提供了依据。目前，NPI-2358正处于治疗癌症的临床前开发阶段。［1］

细胞活力测定[1]
细胞类型： HUVEC 细胞
测试浓度： 2 nM、10 nM、20 nM 和 200 nM
孵育时间：30 分钟
实验结果：低浓度（2 nM、10 nM）快速诱导 HUVEC 中微管蛋白解聚。

Animal/Disease Models: Female CDF1 mice (10-14weeks old) with C3H mammary carcinoma; Female C3H/HeJ mice with KHT sarcoma cells (8-weeks-old)[3]
Doses: 0 mg/kg, 1.5 mg/kg , 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 12.5 mg/kg, 15 mg/kg; 0.02 mL/g mouse body weight in CDF1 mice and 0.01 mL/g body weight for C3H /HeJ mice
Route of Administration: intraperitoneal (ip)injection; 0 huor, 1 huor, 3 hrs (hours), 6 huors, 24 huors
Experimental Results: Induced a time- and dose-dependent decrease in tumour perfusion. The KHT sarcoma was more sensitive than the C3H tumour to the anti -tumor, while radiation response was enhanced in both models.

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Patients received a weekly infusion of plinabulin for 3 of every 4 weeks. A dynamic accelerated dose titration method was used to escalate the dose from 2 mg/m² to the RP2D, followed by enrollment of an RP2D cohort. Safety, pharmacokinetic, and cardiovascular assessments were conducted, and Dynamic contrast-enhanced MRI (DCE-MRI) scans were performed to estimate changes in tumor blood flow.[2]

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Foot implanted C3H mammary carcinomas or leg implanted KHT sarcomas were used, with plinabulin injected intraperitoneally. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measurements were made with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) on a 7-tesla magnet. Treatment response was assessed using regrowth delay (C3H tumours), clonogenic survival (KHT sarcomas) or histological estimates of necrosis for both models.[3]

[1]. NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent. Anticancer Drugs. 2006 Jan;17(1):25-31.

[2]. Phase 1 First-in-Human Trial of the Vascular Disrupting Agent Plinabulin (NPI-2358) in Patients with Solid Tumors or Lymphomas Clin Cancer Res. 2010 Dec 1;16(23):5892-9.

[3]. Vascular effects of plinabulin (NPI-2358) and the influence on tumour response when given alone or combined with radiation. Int J Radiat Biol. 2011 Nov;87(11):1126-34.

Plinabulin is a member of the class of 2,5-diketopiperazines that is piperazine-2,5-dione substituted by benzylidene and (5-tert-butyl-1H-imidazol-4-yl)methylidene groups at positions 3 and 6, respectively. It is a vascular disrupting agent and a microtubule destabalising agent which was in clinical trials (now discontinued) for the treatment of non-small cell lung cancer. It has a role as a microtubule-destabilising agent, an antineoplastic agent, an apoptosis inducer and an angiogenesis inhibitor. It is a member of 2,5-diketopiperazines, a member of imidazoles, a member of benzenes and an olefinic compound.
Plinabulin is an orally active diketopiperazine derivative with potential antineoplastic activity. Plinabulin selectively targets and binds to the colchicine-binding site of tubulin, thereby interrupting equilibrium of microtubule dynamics. This disrupts mitotic spindle assembly leading to cell cycle arrest at M phase and blockage of cell division. In addition, plinabulin may also inhibit growth of proliferating vascular endothelial cells, thereby disrupting the function of tumor vasculature that further contributes to a decrease in tumor cell proliferation.

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Drug Indication
Investigated for use/treatment in cancer/tumors (unspecified).

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Mechanism of Action
NPI-2358 is a vascular disrupting agent currently in clinical development for the treatment of cancer by Nereus. NPI-2358 is one of over 200 synthetic analogues that were prepared following the discovery of the compound Halimide isolated from a marine fungus. In preclinical models of cancer, including lung, breast, sarcoma, colon and prostate, NPI-2358 demonstrated potent and selective anti-tumor effects in combination with docetaxel and other oncology therapies, as well as single-agent efficacy in a number of orthotopic models. NPI-2358 interacts with soluble beta-tubulin and prevents the polymerization of tubulin without altering dynamic microtubule function of formed microtubules. As demonstrated in preclinical testing, this target profile results in a highly specific nanomolar cytotoxicity while reducing the side effects seen in first-generation VDAs due to cardiotoxicity, hemodynamic changes and neuropathies.

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Plinabulin (NPI-2358) is a vascular disrupting agent that elicits tumor vascular endothelial architectural destabilization leading to selective collapse of established tumor vasculature. Preclinical data indicated plinabulin has favorable safety and antitumor activity profiles, leading to initiation of this clinical trial to determine the recommended phase 2 dose (RP2D) and assess the safety, pharmacokinetics, and biologic activity of plinabulin in patients with advanced malignancies. [2]

C19H20N4O2

336.39

336.158

C, 67.84; H, 5.99; N, 16.66; O, 9.51

714272-27-2

9949641

Light yellow to yellow solid powder

1.3±0.1 g/cm3

730.3±60.0 °C at 760 mmHg

395.5±32.9 °C

0.0±2.4 mmHg at 25°C

1.657

2.66

94.92

3

3

3

25

597

0

CC(C)(C)C1=C(N=CN1)/C=C\2/C(=O)N/C(=C\C3=CC=CC=C3)/C(=O)N2

UNRCMCRRFYFGFX-TYPNBTCFSA-N

InChI=1S/C19H20N4O2/c1-19(2,3)16-13(20-11-21-16)10-15-18(25)22-14(17(24)23-15)9-12-7-5-4-6-8-12/h4-11H,1-3H3,(H,20,21)(H,22,25)(H,23,24)/b14-9-,15-10-

(3E,6E)-3-benzylidene-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione

NPI-2358; Plinabulin; NPI2358; Plinabulin(NPI-2358); NPI 2358; NPI-2358 (Plinabulin); (3z,6z)-3-Benzylidene-6-[(5-Tert-Butyl-1h-Imidazol-4-Yl)methylidene]piperazine-2,5-Dione; 986FY7F8XR; NPI 2358;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.43 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 25.0 mg/mL澄清DMSO储备液加入到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。

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配方 2 中的溶解度: 2.5 mg/mL (7.43 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 25.0 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。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (7.43 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
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；
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