| CAS |
No.191732-72-6 |
| 中文名称 |
来那度胺(10mM in DMSO,无菌） |
| 英文名称 |
Lenalidomide(10mM in DMSO，Sterile） |
| 分子式 |
C13H13N3O3 |
| 分子量 |
259.26 |
| 溶解性 |
请根据自己的实验要求使用。 |
| 外观(性状) |
无菌溶液 |
| 储存条件 |
Stroe at -20℃，6 months. |
| 靶点 |
E3 Ligase;TNF-α |
| 通路 |
Ubiquitin;Apoptosis |
| 背景说明 |
Lenalidomide是一种TNF-α分泌抑制剂；还是CRBN的配体，它通过CRBN-CRL4泛素连接酶引起两个淋巴样转录因子IKZF1和IKZF3的选择性泛素化和降解。 |
| 生物活性 |
Lenalidomide (CC-5013)， a derivative of Thalidomide， acts as molecular glue. Lenalidomide is an orally active immunomodulator. Lenalidomide (CC-5013) is a ligand of ubiquitin E3 ligase cereblon (CRBN)， and it causes selective ubiquitination and degradation of two lymphoid transcription factors， IKZF1 and IKZF3， by the CRBN-CRL4 ubiquitin ligase. Lenalidomide (CC-5013) specifically inhibits growth of mature B-cell lymphomas， including multiple myeloma， and induces IL-2 release from T cells.[1-7] |
| In Vitro |
Lenalidomide is potent in stimulating T cell proliferation and IFN-γ and IL-2 production. Lenalidomide has been shown to inhibit production of pro inflammatory cytokines TNF-α， IL-1， IL-6， IL-12 and elevate the production of anti-inflammatory cytokine IL-10 from human PBMCs. Lenalidomide downregulates the production of IL-6 directly and also by inhibiting multiple myeloma (MM) cells and bone marrow stromal cells (BMSC) interaction， which augments the apoptosis of myeloma cells[2]. Dose-dependent interaction with the CRBN-DDB1 complex is observed with Thalidomide， Lenalidomide and Pomalidomide， with IC50 values of ~30 μM， ~3 μM and ~3 μM， respectively， These reduced CRBN expression cells (U266-CRBN60 and U266-CRBN75) are less responsive than the parental cells to antiproliferative effects Lenalidomide across a dose-response range of 0.01 to 10 μM[3]. Lenalidomide， a thalidomide analog， functions as a molecular glue between the human E3 ubiquitin ligase cereblon and CKIα is shown to induce the ubiquitination and degradation of this kinase， thus presumably killing leukemic cells by p53 activation[5]. |
| In Vivo |
The toxicity of Lenalidomide doses up to 15， 22.5， and 45 mg/kg via IV， IP， and PO routes of administration. Limited by solubility in our PBS dosing vehicle， these maximum achievable Lenalidomide doses are well tolerated with the exception of one mouse death (of four total dosed) at the 15 mg/kg IV dose. Notably， no other toxicities are observed in the study at IV doses of 15 mg/kg (n=3) or 10 mg/kg (n=45) or at any other dose level through IV， IP， and PO routes[4]. |
| 细胞实验 |
Cell lines NCI-H929 and U266， and DF15 cells are grown in RPMI-I640 medium containing 10% (V/V) heat-inactivated fetal bovine serum supplemented with 2 mM glutamine. To produce Lenalidomide resistant cell lines， NCI-H929 cells are treated continuously (fresh Lenalidomide is added every 3-4 days) with control (final 0.1% DMSO) or low-dose Lenalidomide (1 μM) for 2 months until the proliferation of cells is no longer inhibited by Lenalidomide (1 μM)， as determined by cell viability (Vi-cell XR cell viability analyzer)， cell proliferation by flow cytometry and cell cycle analysis (propidium iodide staining). After acquisition of resistance to 1 μM， the resistant H929 cell lines are treated with Lenalidomide (10 μM) for a further 4 months. After this period of time， the cell cultures achieved fully establish resistance up to high-dose Lenalidomide (30 μM). Prior to the experiments described here， H929 Lenalidomide-resistant cells are taken out of culture with compounds for 5-7 days before use[3]. |
| 动物实验 |
Mice[4]Imprinting control region (ICR) mice 8-10 weeks of age are used. Lenalidomide is incompletely soluble at 3.5 mg/mL and above in PBS containing 1% HCl， as visible particulates remained after thorough mixing. Therefore 3 mg/mL is selected as the maximum dosing solution concentration (with no visible particulates). Single， individual mice are initially dosed with 3， 10， or 15 mg/kg IV; 4.5， 15， or 22.5 mg/kg IP; and 9， 30， or 45 mg/kg PO. Additional mice (n=4) are then evaluated at the maximum dose achievable by volume and solubility of Lenalidomide in the dosing solution. All mice are monitored closely for 1 h and re-evaluated for toxicities 3， 6， and 24 h postdose[4]. |
| 数据来源文献 |
[1]. Kr?nke J， et al. Lenalidomide induces degradation of IKZF1 and IKZF3. Oncoimmunology. 2014 Jul 3;3(7):e941742.
[2]. Kotla V， et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009 Aug 12;2:36.
[3]. Lopez-Girona A， et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012 Nov;26(11):2326-35.
[4]. Rozewski DM， et al. Pharmacokinetics and tissue disposition of lenalidomide in mice. AAPS J. 2012 Dec;14(4):872-82.
[5]. Minzel W， et al. Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell. 2018 Sep 20;175(1):171-185.e25.
[6]. Nagashima， Takeyuki， et al. PHARMACEUTICAL COMPOSITION COMPRISING BICYCLIC NITROGEN-CONTAINING AROMATIC HETEROCYCLIC AMIDE COMPOUND AS ACTIVE INGREDIENT. Patent. 20170360780A1.
[7]. Omran A， et al. Effects of MRP8， LPS， and lenalidomide on the expressions of TNF-α ， brain-enriched， and inflammation-related microRNAs in the primary astrocyte culture. ScientificWorldJournal. 2013 Sep 21;2013:208309. |
| 规格 |
0.1ml 0.3ml 0.5ml 1ml 1.5ml |
| 单位 |
瓶 |
中文
英语
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