JNJ-26854165 (Serdemetan)

Catalog No.S1172

JNJ-26854165 (Serdemetan) acts as a HDM2 ubiquitin ligase antagonist and also induces early apoptosis in p53 wild-type cells, inhibits cellular proliferation followed by delayed apoptosis in the absence of functional p53. Phase 1.

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JNJ-26854165 (Serdemetan) Chemical Structure

JNJ-26854165 (Serdemetan) Chemical Structure
Molecular Weight: 328.41

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Product Description

Biological Activity

Description JNJ-26854165 (Serdemetan) acts as a HDM2 ubiquitin ligase antagonist and also induces early apoptosis in p53 wild-type cells, inhibits cellular proliferation followed by delayed apoptosis in the absence of functional p53. Phase 1.
Targets p53 [1]
(Cell-free assay)
HDM2 [1]
(Cell-free assay)
Mdm2 [2]
(Cell-free assay)
In vitro JNJ 26854165 is a novel tryptamine derivative which activates p53 and acts as a HDM2 ubiquitin ligase antagonist. JNJ 26854165 inhibits cell growth and induces apoptosis in leukemia cell lines with IC50 values of 0.24, 0.33, 0.32 and 0.44 μM at 72 hours for OCI-AML-3, MOLM-13, NALM-6 and REH cells, respectively. In addition, JNJ 26854165 accelerates proteasome-mediated degradation of p21 and antagonizes the transcriptional induction of p21 by p53. It also induces S-phase delay and upregulates E2F1 expression in p53 mutant cells, resulting in preferential apoptosis of S-phase cells. [1] JNJ 26854165 is an oral Mdm2 inhibitor which can inhibit the interaction of Mdm2-p53 complex with the proteasome and increase p53 levels by binding to RING domain of Mdm2. [2] A recent study shows that JNJ 26854165 inhibits clonogenic survival in four human cancer cell lines: H460, A549, p53-WT-HCT116, and p53-null-HCT116. [3]
In vivo JNJ 26854165 leads to significant differences in EFS distribution in 17 of the 36 (47%) evaluable solid tumor xenografts and in 5 of 7 (71%) of the evaluable ALL xenografts using a dose of 20 mg/kg administered via oral gavage daily for 5 days, repeated for 6 weeks. [4]
Features

Protocol(Only for Reference)

Cell Assay: [1]

Cell lines OCI-AML-3, MOLM-13, NB4 and U937 cells
Concentrations 0-10 μM
Incubation Time 72 hours
Method Cell lines are maintained in RPMI 1640 medium containing 10% heat-inactivated fetal calf serum (FCS). OCI-AML-3, MOLM-13, NB4 and U937 cells are derived from acute myelogenous leukemia (AML) patients, K562 from a chronic myelogenous leukemia (CML) patient in blast crisis, and NALM-6, REH, P12-ICHIK

Animal Study: [4]

Animal Models CB17SC scid-/- female mice.
Formulation JNJ-26854165 is dissolved in DMSO and then diluted in water.
Dosages ≤20 mg/kg
Administration Administered via p.o.

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

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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] Kojima K, et al. Mol Cancer Ther. 2010, 9(9), 2545-2557.

[2] Yuan Y, et al. J Hematol Oncol. 2011, 4:16.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-25)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00676910 Completed Neoplasms Johnson & Johnson Pharmaceutical Research & Development,  ...more Johnson & Johnson Pharmaceutical Research & Development, L.L.C. November 2006 Phase 1

Chemical Information

Download JNJ-26854165 (Serdemetan) SDF
Molecular Weight (MW) 328.41
Formula

C21H20N4

CAS No. 881202-45-5
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 66 mg/mL (200.96 mM)
Ethanol 2 mg/mL (6.08 mM)
Water <1 mg/mL (<1 mM)
In vivo 1% DMSO+30% polyethylene glycol+1% Tween 80 30 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 N1-(2-(1H-indol-3-yl)ethyl)-N4-(pyridin-4-yl)benzene-1,4-diamine

Customer Product Validation(6)


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Rating
Source Sci Rep 2014 4, 4663. JNJ-26854165 (Serdemetan) purchased from Selleck
Method Immunofluorescence
Cell Lines MCF10A, HCC1937, MDA-MB-231 cells
Concentrations 1–5 μM
Incubation Time 48 h
Results Phase contrast images (upper row)demonstrate an epithelial cobblestone-like (MCF10A and HCC1937) andmesenchymal (MDA-MB-231) morphology of human basal mammary celllines. In cobblestone-like cells, DNp63 is excluded from nucleoli(arrowheads, second row). In mesenchymal-like cells, DNp63 is found innucleoli (arrow). Functional inactivation of DNp63 using HDAC1inhibitor trichostatin A (1TSA, third row) leads to a relocation of DNp63into nucleoli in all cell lines.

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Rating
Source Sci Rep 2014 4, 4663. JNJ-26854165 (Serdemetan) purchased from Selleck
Method Immunofluorescence
Cell Lines lumenal MCF7 cells
Concentrations 10 uM
Incubation Time 72 h
Results Serdemetan treatment increased the expression level of a basal marker DNp63 in lumenal MCF7 cells almost 10-fold, which located in the nucleoplasm, but not in nucleoli.

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Rating
Source Sci Rep 2014 4, 4663. JNJ-26854165 (Serdemetan) purchased from Selleck
Method Western blot
Cell Lines lumenal MCF7 cells
Concentrations 10 uM
Incubation Time 72 h
Results Inhibition of MDM2either with Serdemetan or a siRNA suppressed BRCA1 revealing a strong correlation between these two genes.

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Rating
Source Mol Pharmacol 2014 85(3), 408-19. JNJ-26854165 (Serdemetan) purchased from Selleck
Method Assessment of Autophagy
Cell Lines T24 cells
Concentrations 2 uM
Incubation Time 24 h
Results Sildenafil rapidly and significantly enhanced the amount of DNA damage caused by doxorubicin or mitomycinC as judged in Comet assays.

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Rating
Source J Nat Med 2013 10.1007/s11418-014-0825-0. JNJ-26854165 (Serdemetan) purchased from Selleck
Method Western blot
Cell Lines Molt-4 cells
Concentrations 40 uM
Incubation Time 12 h
Results Effect of Valsartan on phosphorylation of p38 MAPK.

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Rating
Source Curr Protoc Chem Biol 2013 5(3), 195-212. JNJ-26854165 (Serdemetan) purchased from Selleck
Method qHTS
Cell Lines TMD8 cells
Concentrations
Incubation Time 24 h
Results Treatmentwith Plinabulin resulted in an increase in caspase positivity.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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