Lenalidomide (CC-5013)

Lenalidomide (CC-5013) is a TNF-α secretion inhibitor with IC50 of 13 nM.

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Lenalidomide (CC-5013) Chemical Structure

Lenalidomide (CC-5013) Chemical Structure
Molecular Weight: 259.26

Validation & Quality Control

Customer Reviews(4)

Quality Control & MSDS

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  • Research Area
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Product Description

Biological Activity

Description Lenalidomide (CC-5013) is a TNF-α secretion inhibitor with IC50 of 13 nM.
Targets TNF-α [1]
IC50 13 nM
In vitro Lenalidomide strongly induces IL-2 and sIL-2R production. Lenalidomide-induced tyrosine phosphorylation of CD28 on T cells is followed by a down-stream activation of NF-κB. [2] Lenalidomide and pomalidomide inhibits autoubiquitination of CRBN in HEK293 T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplifies pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for Lenalidomide resistance in H929 myeloma cell lines is accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and Lenalidomide, CRBN protein is undetectable. [3] Lenalidomide prevents induction of defects by down-regulating tumor cell inhibitory molecule expression. Lenalidomide prevents induction of tumor-induced T cell lytic synapse dysfunction. Lenalidomide treatment blocks CLL cell-induced T cell actin synapse dysfunction, mimicks antibody blockade, and down-regulates expression of CLL inhibitory ligands and their receptors on T cells. Lenalidomide treatment prevents tumor-induced immune suppression in FL, DLBCL, HL, MM, SCC, and OC and down-regulates immunosuppressive ligand expression on all tumor cells examined. CTL killing function significantly increases following antibody blockade of CLL inhibitory ligands or Lenalidomide treatment compared to control treatments. Treatment of autologous CLL-T cell co-cultures with Lenalidomide reverses impaired CD8+ T cell lytic synapse formation and granzyme B trafficking. [4]
In vivo The induction of angiogenesis by bFGF is significantly inhibited by oral treatment of Lenalidomide in a dose-dependent manner. Lenalidomide significantly decreases the percentage of vascularized area from 5.16% (control group) to 2.58% (50 mg/kg). Lenalidomide significantly reduces the calculated total MVL from 21.07 (control) to 8.11 (50 mg/kg). Lenalidomide significantly inhibites HUVEC migration through the fibronectin-coated membranes towards 0.1 ng/mL of bFGF at 100 μM, 1 ng/mL of VEGF at concentrations of 10 μM and 100 μM. [5]
Features

Protocol(Only for Reference)

Kinase Assay:

[1]

Assay for inhibition of TNF synthesis by human PBMCs Human PBMCs from normal donors are obtained by Ficoll−Hypaque density centrifugation. Cells (106 cells/mL) are cultured in RPMI supplemented with 10 AB+ serum, 2 mM l-glutamine, 100 U/mL penicillin, and 100 μg/mL streptomycin. Lenalidomide is dissolved in DMSO at 20 mg/mL; further dilution is done with culture medium. The final DMSO concentration in all assays including the controls is 0.25%. Lenalidomide is added to cells 1 hour prior to the addition of LPS. PBMCs (106 cells/mL) are stimulated with 1 μg/mL of LPS from Salmonella minnesota R595. Cells, in triplicate, are incubated with LPS for 18−20 hours at 37 °C in 5% CO2. Supernatants are then harvested and assayed for cytokine levels. In some experiments, supernatants are kept frozen at −70 °C until use. Cell viability is assayed by Trypan blue exclusion dye method. The concentration of TNFα in the culture supernatants is determined by ELISA. Lenalidomide is assayed in a minimum of three separate experiments. Percent inhibition is determined as 100 × [1 − (cytokine(experimental)/cytokine(control))].

Animal Study:

[5]

Animal Models Adult male Sprague-Dawley rats bearing HUVECs cells
Formulation 0.5% DMSO
Dosages 50 mg/kg and 250 mg/kg
Administration Administered via i.p.
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, , 5 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Muller GW, et al. Bioorg Med Chem Lett, 1999, 9(11), 1625-1630.

[2] Zangari M, et al. Expert Opin Investig Drugs. 2005, 14(11), 1411-1418.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-20)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02225275 Not yet recruiting Leukemia M.D. Anderson Cancer Center|Genentech|Celgene Corporation December 2014 --
NCT02232516 Not yet recruiting Adult Nasal Type Extranodal NK/T-cell Lymphoma|Anaplastic Large Cell Lymphoma|Angioimmunoblastic T-cell Lymphoma|Hepatosplenic T-cell Lymphoma|Peri  ...more Adult Nasal Type Extranodal NK/T-cell Lymphoma|Anaplastic Large Cell Lymphoma|Angioimmunoblastic T-cell Lymphoma|Hepatosplenic T-cell Lymphoma|Peripheral T-cell Lymphoma|Stage I Cutaneous T-cell Non-Hodgkin Lymphoma|Stage IA Mycosis Fungoides/Sezary Syndrome|Stage IB Mycosis Fungoides/Sezary Syndrome|Stage II Cutaneous T-cell Non-Hodgkin Lymphoma|Stage IIA Mycosis Fungoides/Sezary Syndrome|Stage IIB Mycosis Fungoides/Sezary Syndrome|Stage III Cutaneous T-cell Non-Hodgkin Lymphoma|Stage IIIA Mycosis Fungoides/Sezary Syndrome|Stage IIIB Mycosis Fungoides/Sezary Syndrome|Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma|Stage IVA Mycosis Fungoides/Sezary Syndrome|Stage IVB Mycosis Fungoides/Sezary Syndrome Northwestern University|Celgene Corporation|National Canc  ...more Northwestern University|Celgene Corporation|National Cancer Institute (NCI) October 2014 Phase 2
NCT02219178 Not yet recruiting Multiple Myeloma ICORG- All Ireland Cooperative Oncology Research Group October 2014 Phase 2
NCT02126553 Not yet recruiting Leukemia M.D. Anderson Cancer Center|Celgene Corporation October 2014 Phase 2
NCT01924169 Not yet recruiting Hematologic Disorder M.D. Anderson Cancer Center|Celgene Corporation October 2014 Phase 2

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Chemical Information

Download Lenalidomide (CC-5013) SDF
Molecular Weight (MW) 259.26
Formula

C13H13N3O3

CAS No. 191732-72-6
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 52 mg/mL (200 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 5 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Research Area

Customer Reviews (4)


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Rating
Source Clin Cancer Res 2011 17, 5311-21. Lenalidomide (CC-5013) purchased from Selleck
Method MTT assays
Cell Lines MM.1S cells
Concentrations 1-5 μM
Incubation Time 48 h
Results The combination of low concentrations of MLN2238 and lenalidomide triggered synergistic anti-MM activity, with acombination index (CI) < 1.0.

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Rating
Source Obesity 2012 20, 2174-85. Lenalidomide (CC-5013) purchased from Selleck
Method Western Blot
Cell Lines ob/ob mice
Concentrations 50 mg/kg/day
Incubation Time 3 d
Results Although lenalidomide itself did not exert any effect on the expression of these proteins, it significantly attenuated or ablated obesity-induced upregulation of TNF-α, IL-6, Fas, and cleaved caspase-3 without any effect on FasL.

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Rating
Source Harvard Medical School. Lenalidomide (CC-5013) purchased from Selleck
Method AnnexinV/PI staining, Western blotting
Cell Lines MM.1S cells
Concentrations 2 μM
Incubation Time 0-72 h
Results The analysis showed an increase (55.7%) of cells in early and late apoptosis after 72 hours of exposure to combined therapy. Combined AT9283 and lenalidomide increased cleavage of caspase-8 and PARP. Using western blot analysis to delineate the molecular mechanism underlying this combination, we found that combination treatment resulted in downregulation of pSTAT3 and pERK following 4 hours of treatment.

Click to enlarge
Rating
Source Harvard Medical School. Lenalidomide (CC-5013) purchased from Selleck
Method Western blotting, Cell proliferation assay
Cell Lines MM.1S cells
Concentrations 2 μM
Incubation Time 4/48 h
Results Combined therapy inhibited 3H-TdR uptake of MM.1S cells cultured in the presence of BMSCs. Interestingly, consistent with this data, We observed that AT9283 plus lenalidomide downregulated the expression of the p-STAT3 and p-ERK in MM.1S cells cultured with BMSCs.

Product Citations (17)

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