HDAC; HIV-1

体外活性：LBH589 以时间和剂量依赖性方式诱导 MOLT-4 和 Reh 细胞凋亡。此外，LBH589 在 MOLT-4 中比在 Reh 细胞中更有效。 LBH589 在 48 小时内以剂量依赖性方式显着阻止 MOLT-4 和 Reh 细胞的生长。与对照细胞相比，LBH589 处理导致细胞周期 G2/M 期细胞数量增加 2 至 3 倍。 LBH589 与诱导组蛋白 H3K9 和组蛋白 H4K8 乙酰化以及以剂量依赖性方式降低 c-Myc 表达水平相关。 LBH589 治疗还增加了 p21 表达水平。在 Reh 细胞中以最低剂量 (10 nM) 初始增加后，LBH589 治疗还会降低 c-Myc 水平。此外，LBH589 还能显着提高促凋亡和 DNA 修复基因的 mRNA 水平。 LBH589 诱导 GADD45G 启动子处乙酰化组蛋白 H3 和 H4 水平增加。此外，LBH589 还能抑制非小细胞肺癌细胞系（例如人 H1299、L55 和 A549，IC50 分别为 5 nM、11 nM 和 30 nM）、间皮瘤（例如人 OK-6 和 Ok-5）的生长。 IC50 分别为 5 nM 和 7 nM）和小细胞肺癌细胞系（例如人 RG-1 和 LD-T，IC50 分别为 4 nM 和 5 nM）。激酶测定：Panobinostat 是一种非选择性组蛋白脱乙酰酶 (HDAC) 抑制剂。细胞测定：使用膜联蛋白 V-FITC 细胞凋亡检测试剂盒 I，用膜联蛋白 V 和碘化丙啶对未处理和 LBH589 处理的细胞 [人 Ph-急性淋巴细胞白血病 MOLT-4（T 细胞）和 Reh（前 B 细胞）] 进行染色。通过流式细胞术测定凋亡细胞和非存活细胞的百分比。使用 CyAn ADP 紫细胞计数器收集至少 5 × 104 个细胞。计算细胞凋亡百分比时考虑所有膜联蛋白 V 阳性细胞加上膜联蛋白 V/PI 阳性细胞；考虑所有膜联蛋白 V 阳性细胞加上 PI 阳性细胞以及膜联蛋白 V/PI 阳性细胞，计算细胞活力损失百分比。

在肺癌和间皮瘤动物模型中，LBH589 显着降低肿瘤生长 62%。 LBH589 对于免疫功能正常的小鼠和严重联合免疫缺陷小鼠同样有效，这表明 LBH589 对肿瘤生长的抑制并非由于直接的免疫作用。每日 LBH589，每周 5 天以 20 mg/kg 腹腔注射，导致生长平均下降 70%。与相应的对照肿瘤相比，LBH589导致H526衍生的肿瘤减少53%，BK-T衍生的肿瘤减少81%，RG-1衍生的肿瘤减少76%，以及BK-T衍生的肿瘤减少70%。 H69衍生的肿瘤。与在相同条件和剂量下治疗的 NSCLC 和内观衍生异种移植肿瘤中缺乏肿瘤消退迹象相反，LBH589 导致 SCLC 衍生肿瘤和 RG-1 衍生肿瘤的肿瘤显着消退。

Panobinostat 是一种非选择性组蛋白脱乙酰酶 (HDAC) 抑制剂。

annexin V-FITC 细胞凋亡检测试剂盒用于对未经处理和 LBH589 处理的人 Ph-急性淋巴细胞白血病 MOLT-4（T 细胞）和 Reh（前 B 细胞）细胞进行染色。我。流式细胞术用于计算非存活细胞和凋亡细胞的百分比。使用 CyAn ADP 紫细胞计数器，至少获得 5 × 10⁴ 细胞。通过将所有膜联蛋白 V 阳性、PI 阳性和膜联蛋白 V/PI 阳性细胞加在一起来确定细胞凋亡和细胞活力的百分比。此外，通过将所有膜联蛋白 V 阳性、PI 阳性细胞加在一起来计算细胞活力的百分比。阳性细胞和膜联蛋白 V/PI 阳性细胞。

Absorption, Distribution and Excretion
After a 20 mg dose, panobinostat was quickly absorbed with a time to maximum absorption of 2 hours.

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Metabolism / Metabolites
Panobinostat was extensively metabolized to 77 metabolites. Unchanged panobinostat recovered in urine and feces was 2% and 3%, respectively. Primary metabolic pathways of panobinostat are reduction, hydrolysis, oxidation, and glucuronidation processes. CYP and non-CYP enzymes were found to play significant role in metabolism, CYP2D6 and CYP2C19 playing minor roles.

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Biological Half-Life
30 hours

Hepatotoxicity
Most clinical trials of panobinostat have not reported rates of serum enzyme elevations during therapy and it is typically given in combination with other antineoplastic agents that can cause serum ALT and AST elevations. In the large controlled trial of panobinostat vs placebo in combination with bortezomib and dexamethasone, ALT elevations occurred in similar proportion of patients receiving panobinostat (31%) as placebo (38%) and values above 5 times the upper limit of normal were uncommon (1.8% and 1.3%). In addition, there have been no reports of clinically apparent liver injury with jaundice associated with panobinostat therapy. Thus, panobinostat appears to have little hepatotoxic potential and liver injury from panobinostat must be quite rare, if it occurs at all.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

[1]. Blood . 2008 May 15;111(10):5093-100.

[2]. Mol Cancer Ther . 2009 Aug;8(8):2221-31.

[3]. Haematologica . 2010 May;95(5):794-803.

[4]. Cancer Res . 2006 Jun 1;66(11):5781-9.

[5]. Cancer Lett . 2009 Aug 8;280(2):233-41.

Panobinostat is a hydroxamic acid obtained by formal condensation of the carboxy group of (2E)-3-[4-({[2-(2-methylindol-3-yl)ethyl]amino}methyl)phenyl]prop-2-enoic acid with the amino group of hydroxylamine. A histone deacetylase inhibitor used (as its lactate salt) in combination with bortezomib and dexamethasone for the treatment of multiple myeloma. It has a role as an EC 3.5.1.98 (histone deacetylase) inhibitor, an antineoplastic agent and an angiogenesis modulating agent. It is a hydroxamic acid, a member of cinnamamides, a secondary amino compound and a methylindole. It is a conjugate base of a panobinostat(1+).
Panobinostat is a drug that was previously approved by the U.S. Food and Drug Administration (FDA) under the brand name Farydak for the treatment of a certain type of cancer. Panobinostat is currently being studied as an investigational drug as part of a strategy to cure HIV infection. As an investigational HIV therapy, panobinostat belongs to a group of drugs called latency-reversing agents.
Panobinostat is an oral deacetylace (DAC) inhibitor approved on February 23, 2015 by the FDA for the treatment of multiple myeloma. The approval was accelerated based on progression-free survival, therefore confirmatory trials by the sponsor to demonstrate clinical efficacy in multiple myeloma treatment are in progress of being conducted. Panobinostat is marketed by Novartis under the brand name Farydak. Panobinostat acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor) and it is the most potent DAC inhibiting agent available on the market.
Histone deacetylase (hdac) inhibitor is a Histone Deacetylase Inhibitor. The mechanism of action of histone deacetylase (hdac) inhibitor is as a Histone Deacetylase Inhibitor, and Cytochrome P450 2D6 Inhibitor.
Panobinostat is an oral histone deacetylase inhibitor and antineoplastic agent that is approved for use in combination with other agents in refractory or relapsed multiple myeloma. Panobinostat is associated with modest rate of minor serum enzyme elevations during therapy, but has not been linked to cases of clinically apparent liver injury.
Panobinostat is a cinnamic hydroxamic acid analogue with potential antineoplastic activity. Panobinostat selectively inhibits histone deacetylase (HDAC), inducing hyperacetylation of core histone proteins, which may result in modulation of cell cycle protein expression, cell cycle arrest in the G2/M phase and apoptosis. In addition, this agent appears to modulate the expression of angiogenesis-related genes, such as hypoxia-inducible factor-1alpha (HIF-1a) and vascular endothelial growth factor (VEGF), thus impairing endothelial cell chemotaxis and invasion. HDAC is an enzyme that deacetylates chromatin histone proteins.
An indole and hydroxamic acid derivative that acts as a HISTONE DEACETYLASE inhibitor. It is used as an antineoplastic agent in combination with BORTEZOMIB and DEXAMETHASONE for the treatment of MULTIPLE MYELOMA.
See also: Panobinostat Lactate (active moiety of).

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Drug Indication
Panobinostat is indicated in the treatment of multiple myeloma in combination with dexamethasone and bortezomib in patients who have received 2 previous treatment regimens including bortezomib and an immunomodulatory agent. This indication is approved by accelerated approval based on progression free survival as of February 23, 2015.
FDA Label
Farydak, in combination with bortezomib and dexamethasone, is indicated for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent. Farydak, in combination with bortezomib and dexamethasone, is indicated for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent.

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Mechanism of Action
Panobinostat is a deacetylase (DAC) inhibitor. DACs, also known as histone DACs (HDAC), are responsible for regulating the acetylation of about 1750 proteins in the body; their functions are involved in many biological processes including DNA replication and repair, chromatin remodelling, transcription of genes, progression of the cell-cycle, protein degradation and cytoskeletal reorganization. In multiple myeloma, there is an overexpression of DAC proteins. Panobinostat inhibits class I (HDACs 1, 2, 3, 8), class II (HDACs 4, 5, 6, 7, 9, 10) and class IV (HDAC 11) proteins. Panobinostat's antitumor activity is believed to be attributed to epigenetic modulation of gene expression and inhibition of protein metabolism. Panobinostat also exhibits cytotoxic synergy with bortezomib, a proteasome inhibitor concurrently used in treatment of multiple myeloma.

C21H23N3O2

349.43

349.179

C, 72.18; H, 6.63; N, 12.03; O, 9.16

404950-80-7

404950-80-7;960055-56-5 (lactate); 960055-60-1 (mesylate);960055-50-9 (acetate); 960055-54-3 (fumarate); 960055-57-6

6918837

White to off-white solid powder

1.2±0.1 g/cm3

114-117?C

1.683

3.62

77.15

4

3

7

26

474

0

O=C(/C(/[H])=C(\[H])/C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])N([H])C([H])([H])C([H])([H])C1=C(C([H])([H])[H])N([H])C2=C([H])C([H])=C([H])C([H])=C12)N([H])O[H]

FPOHNWQLNRZRFC-ZHACJKMWSA-N

InChI=1S/C21H23N3O2/c1-15-18(19-4-2-3-5-20(19)23-15)12-13-22-14-17-8-6-16(7-9-17)10-11-21(25)24-26/h2-11,22-23,26H,12-14H2,1H3,(H,24,25)/b11-10+

(E)-N-hydroxy-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide

NVP-LBH589; NVP-LBH 589; LBH589; LBH 589; LBH-589; Panobinostat; Brand name Farydak

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 (7.15 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 (7.15 mM) (饱和度未知) 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), 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 (7.15 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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配方 4 中的溶解度: ≥ 2.5 mg/mL (7.15 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。
*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 5 中的溶解度: 2.5 mg/mL (7.15 mM) in 5% DMSO + 95% (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。
*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 6 中的溶解度: 2% DMSO+48% PEG 300+2% Tween 80+ddH2O: 5mg/mL

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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；
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。