Birinapant Chemical Structure

Birinapant Chemical Structure
Molecular Weight: 806.94

Validation & Quality Control

Customer Product Validation(2)

Quality Control & MSDS

Product Information

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Product Description

Biological Activity

Description Birinapant is a SMAC mimetic antagonist, mostly to cIAP1 with Kd of <1 nM in a cell-free assay, less potent to XIAP. Phase 2.
Targets cIAP1 [1]
(Cell-free assay)
XIAP [1]
(Cell-free assay)
IC50 <1 nM(Kd) 45 nM(Kd)
In vitro Birinapant binds with XIAP and cIAP1 with Kd of 45 and <1 nM, respectively. Birinapant induces cell death as a single agent in TRAIL-insensitive SUM190 (ErbB2-overexpressing) cells (IC50, ~300 nM), and significantly increases potency of TRAIL-induced apoptosis in TRAIL-sensitive SUM149 (triple-negative, EGFR-activated) cells. Birinapant causes rapid cIAP1 degradation, caspase activation, PARP cleavage, and NF-κB activation. [1] Birinapant in combination with TNF-α exhibits a strong antimelanoma effect in vitro. Birinapant in combination with TNF-α(1 ng/mL) inhibits the growth of human melanoma cell lines WTH202, WM793B, WM1366 and WM164 with IC50s of 1.8, 2.5, 7.9 and 9 nM, respectively, while neither compound is effective individually. Birinapant singly treatment induces inhibition on proliferation of WM9 cells with IC50 of 2.4 nM. Birinapant significantly inhibits the target protein cIAP1 and cIAP2 in these cell lines.[2]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
PANC-1NHPXPGtIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NV\qfYVuPTBxMkCwM|UxOCCwTR?=MUCwMVk3KGh?NX\YfHZscW6qaXLpeJMh[2WubDDndo94fGhiaX6gZo91cCC2aX3lJIFv\CCmb4PlJIRmeGWwZHXueEBu[W6wZYK=MXeyOlI2Ojl4OR?=
Molm13 NHfjZ4FHfW6ldHnvckBCe3OjeR?=MmHTNk8zOC9{MECgcm0>MVGyOEBpM3PvcoRm[3KnYYPld{BkUUGSMTDhcoQtKHSxIHGgcZVkcCCuZYPz[ZIh\Xi2ZX70MEBkUUGSMjygZY5lKFiLQWCgeY5l\XJidnHybY92eyClb37kbZRqd26|MofyNlQ2OjZ5OEe=
WTH202NFLNOVZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NIjMSJQ4OiCqMoj0TWM2OD1zLkigcm0tKGOxbXLpcoVlKHerdHigNY5oN22uIGTOSk3PuQ>?M1HvVlI{PDB|NkO0
WM793BNVnEVFg4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NVvMWllPPzJiaB?=M{nFTmlEPTB;Mj61JI5ONCClb33ibY5m\CC5aYToJFFv\y:vbDDUUmYu|rF?NEnWZXEzOzRyM{[zOC=>
WM9M3vxU2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7NVjxNGZUPzJiaB?=M12zZ2lEPTB;Mj60JI5OMnXiNlM1ODN4M{S=
WM9Ml:xS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?M3SyU|czKGh?MXjJR|UxRTJwNzDuUUwh[2:vYnnu[YQhf2m2aDCxcocwdWxiVF7GMe6yNWnGbYNROjN2MEO2N|Q>
WM1366NUjRT2Z1T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M1XoXFczKGh?MWjJR|UxRTdwOTDuUUwh[2:vYnnu[YQhf2m2aDCxcocwdWxiVF7GMe6yNUj4dFBMOjN2MEO2N|Q>
WM164Ml\oS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?Mm\LO|IhcA>?MnXTTWM2OD17IH7NMEBkd22kaX7l[EB4cXSqIEHu[{9udCCWTl[t{tE>MkjmNlM1ODN4M{S=
451LuNHKzWFRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NVrYT5JtPzJiaB?=NYTNcIZwUUN3ME2xOE4zKG6PLDDjc41jcW6nZDD3bZRpKDGwZz;tcEBVVkZvzsG=MWOyN|QxOzZ|NB?=
WM1341DMnnlS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MWC3NkBpNW\OPVhwUUN3ME21O{43KG6PLDDjc41jcW6nZDD3bZRpKDGwZz;tcEBVVkZvzsG=MWGyN|QxOzZ|NB?=
WM3130M33jcGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7MUe3NkBpNWjMd3Z1UUN3ME22OE4{KG6PLDDjc41jcW6nZDD3bZRpKDGwZz;tcEBVVkZvzsG=M1\ISlI{PDB|NkO0
WM1985M2nDfWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7MmS2O|IhcA>?NWrrZ|l6UUN3ME25O{BvVSxiY3;tZolv\WRid3n0bEAydmdxbXygWG5HNc7zNGLMSoUzOzRyM{[zOC=>
WM3854MmTRS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?NHziTI44OiCqMoj1TWM2OD1{Mk[gcm0tKGOxbXLpcoVlKHerdHigNY5oN22uIGTOSk3PuQ>?MnLBNlM1ODN4M{S=

... Click to View More Cell Line Experimental Data

In vivo Birinapant (30 mg/kg) treatment significantly induces abrogation of tumor growth in melanoma xenotransplantation models 451Lu with. [2]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Fluorescence polarization assay The binding affinities of compounds to XIAP and cIAP1 are determined using a fluorogenic substrate and are reported as Kd values. Initially, the dissociation constant (Kd) for the fluorescently labeled modified Smac peptide (AbuRPF-K(5-Fam)-NH2; FP pep-tide) is determined using a fixed concentration of peptide (5 nM) and titrating varying concentrations of protein (0.075–5 μM in half log dilutions). The dose–response curves are produced by a nonlinear least squares fit to a single-site binding model using GraphPad Prism, with 5 nM of FP peptide and 50 nM of XIAP used in the assay. Various concentrations of Smac mimetics (100–0.001 μM in half log dilutions) are added to FP peptide:protein binary complex for 15 min at room temperature in 100μL of 0.1 M potassium phosphate buffer, pH 7.5, containing 100 mg/mL bovine c -globulin. Following incubation, the polarization values are measured on a multi-label plate reader using a 485 nm excitation filter and a 520 nm emission filter.

Cell Assay: [2]

Cell lines Human melanoma cell lines WM9
Concentrations 1 nM-1 μM
Incubation Time 3 days
Method Cells are allowed to attach for 24 hours and subsequently incubated with Birinapant and/or TNF-α for 24 or 72 hours. Then MTS assay is conducted

Animal Study: [2]

Animal Models Human melanoma xenografts 451Lu
Formulation 12.5% Captisol in distilled water
Dosages 30 mg/kg
Administration 3 times per week intraperitoneally

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] Allensworth JL, et al. Breast Cancer Res Treat, 2013, 137(2), 359-371.

[2] Krepler C, et al. Clin Cancer Res, 2013, 19(7), 1784-1794.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-05-07)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02756130 Not yet recruiting Advanced Newly Diagnosed or Recurrent High Grade Serous Carcinomas (HGSC) Jonsson Comprehensive Cancer Center|TetraLogic Pharmaceut  ...more Jonsson Comprehensive Cancer Center|TetraLogic Pharmaceuticals July 2016 Phase 2
NCT02587962 Not yet recruiting Solid Tumors TetraLogic Pharmaceuticals|Merck Sharp & Dohme Corp. December 2015 Phase 1|Phase 2
NCT02288208 Terminated Hepatitis B TetraLogic Pharmaceuticals November 2014 Phase 1
NCT02147873 Terminated Myelodysplastic Syndrome (MDS)|Chronic Myelomonocytic Leukemia (CMML) TetraLogic Pharmaceuticals June 2014 Phase 2
NCT01940172 Completed Relapsed Epithelial Ovarian Cancer|Relapsed Primary Peritoneal Cancer|Relapsed Fallopian Tube Cancer TetraLogic Pharmaceuticals November 2013 Phase 1

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Chemical Information

Download Birinapant SDF
Molecular Weight (MW) 806.94
Formula

C42H56F2N8O6

CAS No. 1260251-31-7
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms TL32711
Solubility (25°C) * In vitro DMSO 100 mg/mL (123.92 mM)
Ethanol 55 mg/mL (68.15 mM)
Water <1 mg/mL (<1 mM)
In vivo 15% Captisol 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 Propanamide, N,N'-[(6,6'-difluoro[2,2'-bi-1H-indole]-3,3'-diyl)bis[methylene[(2R,4S)-4-hydroxy-2,1-pyrrolidinediyl][(1S)-1-ethyl-2-oxo-2,1-ethanediyl]]]bis[2-(methylamino)-, (2S,2'S)-

Customer Product Validation (2)


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Rating
Source British Journal of Cancer, 2015, 112: 1471–1479. Birinapant purchased from Selleck
Method Western Blot
Cell Lines Tumor cells
Concentrations
Incubation Time 5 d
Results Western blot analysis performed on tumour extracts for PARP and cleaved PARP protein expression shows reduction of whole PARP and increase in cleaved PARP protein expression in both treated cohorts at day 5, confirming the downstream signalling as a resul眏Ỵ眐㠞眎膉癠

Click to enlarge
Rating
Source Cell Death Dis 2013 4, e951. Birinapant purchased from Selleck
Method Western blot
Cell Lines H460, A549 and 34LU cells
Concentrations 5 uM
Incubation Time 24 h
Results While treated with birinapant, the major anti-apoptotic protein downregulated in response to HDAC inhibitors, XIAP, which was significantly downregulated after 24 h in H460 and A549 cell lines; interestingly, vorinostat synergized with the XIAP antagonist Birinapant in H460 and A549 cells.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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