TMP195
(Synonyms: TMP195游离态) 目录号 : GC19360
TMP195 是一种有效的选择性 IIa 类 HDAC 抑制剂，对 HDAC4、HDAC5、HDAC7 和 HDAC9 的 IC50 分别为 59 nM、60 nM、26 nM 和 15 nM。
Cas No.:1314891-22-9
Sample solution is provided at 25 µL, 10mM.
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TMP195 is a potent and selective class IIa HDAC inhibitor with IC50s of 59 nM, 60 nM, 26 nM and 15 nM for HDAC4, HDAC5, HDAC7 and HDAC9, respectively[1].
TMP195 promotes the differentiation of human monocytes into antigen presenting cells with IL-4 and GM-CSF in vitro[2]. In renal tubular cell,TMP195 inhibited LPS-induced upregulation of multiple proinflammatory cytokines/chemokines, including intercellular adhesion molecule-1, monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1β, and accumulation of inflammatory cells in the injured kidney[3]. As a potent and selective inhibitor of class IIa histone deacetylase, In vitro TMP195 treatment significantly enhances drug-induced apoptosis and sensitizes multidrug-resistant cancer cells overexpressing ABCB1 or ABCG2 to anticancer drugs[5].TMP195 enhances phagocytic responses to antibody-opsonised CLL cells and E. coli within 30 min of treatment. The enhanced response is phenocopied by knockdown of the Class IIa HDAC, HDAC7, or by low concentrations of the pan-HDAC inhibitor, vorinostat[6].
TMP195 reduces tumor burden and lung metastasis in vivo by regulating macrophage phenotype, changing tumor microenvironment. TMP195 induces recruitment and differentiation of highly phagocytic and stimulating macrophages within tumors. TMP195 significantly reduces proliferating tumor cells, especially in the leading edge of tumor[2].In mice,Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages[4].In C57BL/6J mice, Treatment of L6 myotubes with HDAC inhibitors TMP195 or skeletal muscle with a combination of HDAC and sirtuin inhibitors increased tubulin and pan-protein acetylation, demonstrating effective impairment of HDAC and sirtuin deacetylase activities[7].
References:
[1]: Lobera M, Madauss KP, et,al.Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat Chem Biol. 2013 May;9(5):319-25. doi: 10.1038/nchembio.1223. Epub 2013 Mar 24. PMID: 23524983.
[2]: Guerriero JL, Sotayo A, et,al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature. 2017 Mar 16;543(7645):428-432. doi: 10.1038/nature21409. Epub 2017 Mar 8. PMID: 28273064; PMCID: PMC8170529.
[3]: Zhang W, Guan Y, et,al. Class IIa HDAC inhibitor TMP195 alleviates lipopolysaccharide-induced acute kidney injury. Am J Physiol Renal Physiol. 2020 Dec 1;319(6):F1015-F1026. doi: 10.1152/ajprenal.00405.2020. Epub 2020 Oct 5. PMID: 33017186; PMCID: PMC7792695.
[4]: Asare Y, Campbell-James TA, et,al. Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability. Circ Res. 2020 Aug 28;127(6):811-823. doi: 10.1161/CIRCRESAHA.120.316743. Epub 2020 Jun 17. PMID: 32546048.
[5]: Wu CP, Lusvarghi S, et,al.The Selective Class IIa Histone Deacetylase Inhibitor TMP195 Resensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs. Int J Mol Sci. 2019 Dec 29;21(1):238. doi: 10.3390/ijms21010238. PMID: 31905792; PMCID: PMC6981391.
[6]: Burgess M, Chen YCE, et,al. HDAC7 is an actionable driver of therapeutic antibody resistance by macrophages from CLL patients. Oncogene. 2020 Aug;39(35):5756-5767. doi: 10.1038/s41388-020-01394-w. Epub 2020 Jul 24. Erratum in: Oncogene. 2021 Feb;40(6):1203. PMID: 32709923.
[7]: Martins VF, Begur M, et,al.Acute inhibition of protein deacetylases does not impact skeletal muscle insulin action. Am J Physiol Cell Physiol. 2019 Nov 1;317(5):C964-C968. doi: 10.1152/ajpcell.00159.2019. Epub 2019 Aug 28. PMID: 31461343; PMCID: PMC6879879.
TMP195 是一种有效的选择性 IIa 类 HDAC 抑制剂，对 HDAC4、HDAC5、HDAC7 和 HDAC9 的 IC50 分别为 59 nM、60 nM、26 nM 和 15 nM[1]。 p>
TMP195 在体外通过 IL-4 和 GM-CSF 促进人单核细胞分化为抗原呈递细胞[2]。在肾小管细胞中，TMP195 抑制 LPS 诱导的多种促炎细胞因子/趋化因子的上调，包括细胞间粘附分子-1、单核细胞趋化蛋白-1、肿瘤坏死因子-α；和白细胞介素-1β；以及炎症细胞在肾小管中的积累受伤的肾脏[3]。作为 IIa 类组蛋白脱乙酰酶的有效选择性抑制剂，TMP195 在体外处理显着增强药物诱导的细胞凋亡，并使过度表达 ABCB1 或 ABCG2 的多药耐药癌细胞对抗癌药物敏感[5]。TMP195 增强吞噬细胞治疗后 30 分钟内对抗体调理的 CLL 细胞和大肠杆菌产生反应。通过敲低 IIa 类 HDAC、HDAC7 或低浓度的泛 HDAC 抑制剂伏立诺他[6]，可以表型复制增强的反应。
TMP195 减少肿瘤负荷和体内肺转移通过调节巨噬细胞表型，改变肿瘤微环境。 TMP195 诱导肿瘤内高度吞噬和刺激性巨噬细胞的募集和分化。 TMP195 显着减少增殖的肿瘤细胞，尤其是在肿瘤的前缘[2]。在小鼠中，使用 IIa 类 HDAC 抑制剂 TMP195 对 HDAC9 进行药理学抑制可通过减少内皮细胞活化和白细胞募集来减弱病变形成限制巨噬细胞的促炎反应[4]。在 C57BL/6J 小鼠中，用 HDAC 抑制剂 TMP195 治疗 L6 肌管或用 HDAC 和 sirtuin 抑制剂联合治疗骨骼肌增加微管蛋白和泛蛋白乙酰化，证明 HDAC 和去乙酰化酶活性的有效损伤[7]。
TMP195 在体外通过 IL-4 和 GM-CSF 促进人单核细胞分化为抗原呈递细胞[2]。在肾小管细胞中，TMP195 抑制 LPS 诱导的多种促炎细胞因子/趋化因子的上调，包括细胞间粘附分子-1、单核细胞趋化蛋白-1、肿瘤坏死因子-α；和白细胞介素-1β；以及炎症细胞在肾小管中的积累受伤的肾脏[3]。作为 IIa 类组蛋白脱乙酰酶的有效选择性抑制剂，TMP195 在体外处理显着增强药物诱导的细胞凋亡，并使过度表达 ABCB1 或 ABCG2 的多药耐药癌细胞对抗癌药物敏感[5]。TMP195 增强吞噬细胞治疗后 30 分钟内对抗体调理的 CLL 细胞和大肠杆菌产生反应。通过敲低 IIa 类 HDAC、HDAC7 或低浓度的泛 HDAC 抑制剂伏立诺他[6]，可以表型复制增强的反应。
TMP195 减少肿瘤负荷和体内肺转移通过调节巨噬细胞表型，改变肿瘤微环境。 TMP195 诱导肿瘤内高度吞噬和刺激性巨噬细胞的募集和分化。 TMP195 显着减少增殖的肿瘤细胞，尤其是在肿瘤的前缘[2]。在小鼠中，使用 IIa 类 HDAC 抑制剂 TMP195 对 HDAC9 进行药理学抑制可通过减少内皮细胞活化和白细胞募集来减弱病变形成限制巨噬细胞的促炎反应[4]。在 C57BL/6J 小鼠中，用 HDAC 抑制剂 TMP195 治疗 L6 肌管或用 HDAC 和 sirtuin 抑制剂联合治疗骨骼肌增加微管蛋白和泛蛋白乙酰化，证明 HDAC 和去乙酰化酶活性的有效损伤[7]。
| Kinase experiment [1]: | |
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Preparation Method |
For inhibitor compound testing,Specifically, 5 μL of 5 nM HDAC9 in assay buffer was added to the plates with 100 nL of compounds at various concentration predispensed in 100% DMSO.The final concentrations of HDAC9 and class IIa HDAC substrate in the plate were 2.5 nM and 4.5 μM, respectively. After incubation for 45 min at room temperature, 10 mL of 2 developer solution was added per well. |
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Reaction Conditions |
10 mM TMP195 ( final concentration)for 45min |
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Applications |
TMP195 is a selective class IIa histone deacetylase (HDAC) inhibitor with Kis of 59, 60, 26, 15 nM for HDAC4, HDAC5, HDAC7 and HDAC9, respectively. |
| Cell experiment [2]: | |
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Cell lines |
Human monocytes |
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Preparation Method |
Monocytes were differentiated into antigen presenting cells in medium with penicillin and streptomycin in the presence of 0.1% (v/v) DMSO or 300 nM TMP195 for 5 days. |
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Reaction Conditions |
300 nM TMP195 for 5 days |
|
Applications |
TMP195 promotes the differentiation of human monocytes into antigen presenting cells with IL-4 and GM-CSF in vitro.· |
| Animal experiment [2]: | |
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Animal models |
Mmtv-pymt transgenic mice |
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Preparation Method |
Mice were treated with intraperitoneal (i.p.) injections of 50 μl of the vehicle dimethyl sulfoxide (DMSO) or 50 μl of TMP195 dissolved in 100% DMSO at a final concentration of 50 mg per kg daily. |
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Dosage form |
50 mg /kg TMP195 for two weeks（Intraperitoneal injection＿/p> |
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Applications |
TMP195 reduces tumor burden and lung metastasis in vivo by regulating macrophage phenotype, changing tumor microenvironment. TMP195 induces recruitment and differentiation of highly phagocytic and stimulating macrophages within tumors. TMP195 significantly reduces proliferating tumor cells, especially in the leading edge of tumor. Induction of antitumor macrophages by TMP195 has been shown to enhance the efficacy and persistence of standard chemotherapy regimens and checkpoint blockade immunotherapy in a murine model of breast cancer |
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References: [1].Lobera M, Madauss KP, et,al. Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat Chem Biol. 2013 May;9(5):319-25. doi: 10.1038/nchembio.1223. Epub 2013 Mar 24. PMID: 23524983. [2].Guerriero JL, Sotayo A, et,al.Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature. 2017 Mar 16;543(7645):428-432. doi: 10.1038/nature21409. Epub 2017 Mar 8. PMID: 28273064; PMCID: PMC8170529. |
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| Cas No. | 1314891-22-9 | SDF | |
| 别名 | TMP195游离态 | ||
| Canonical SMILES | O=C(NCC(C)(C)C1=COC(C2=CC=CC=C2)=N1)C3=CC(C4=NOC(C(F)(F)F)=N4)=CC=C3 | ||
| 分子式 | C23H19F3N4O3 | 分子量 | 456.42 |
| 溶解度 | DMSO : ≥ 100 mg/mL (219.10 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.191 mL | 10.9548 mL | 21.9096 mL |
| 5 mM | 0.4382 mL | 2.191 mL | 4.3819 mL |
| 10 mM | 0.2191 mL | 1.0955 mL | 2.191 mL |
| 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） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 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GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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，
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 saline，混匀澄清。
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
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