Birinapant

Catalog No.S7015 Synonyms: TL32711

Birinapant Chemical Structure

Molecular Weight(MW): 806.94

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.

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Cited by 15 Publications

5 Customer Reviews

  • Western blot from tumours harvested at day 5 after treatment showing an increase in PARP cleavage in the irinotecan-treated group.

    British Journal of Cancer, 2015, 112: 1471–1479. Birinapant purchased from Selleck.

  • Western blot analysis of XIAP and cIAP1 expression and PARP cleavage in H460, A549 and 34LU cells pre-treated with vorinostat or entinostat for 6h followed by the SMAC mimetic birinapant for 24h.

    Cell Death Dis 2013 4, e951. Birinapant purchased from Selleck.

  • Cell survival of macrophages was measured by MTT assay after(a) 24 h and (b) 2 or 4 h posttreatment of cells with SMAC mimetic (BP, 10 μM) with or without zVAD-fmk (50 μM) or Nec-1 (10 μM). Graphs show the percentage of surviving cells relative to the corresponding vehicle control. These graphs are representative of three biological replicates each carried out in triplicate.

    Cell Death Differ, 2016, 23(10):1628-37.. Birinapant purchased from Selleck.

  • (a) Apoptosis assessed morphologically after DAPI staining (top panels) and by caspase 3/7 activation (bottom panels) in human cholangiocyte cell lines H69 and NHC, and the human breast cancer cell line MDA-MB-231, incubated for 24 h with or without (cnt) the SMAC mimetic TL32711 (1 μM), in the presence or absence of neutralizing antibodies against TNFα (1 μg/ml) or FasL (1 μg/ml), or recombinant TRAIL-R2:Fc (1 μg/ml).

    Cell Death Dis, 2017, 8(1):e2535. Birinapant purchased from Selleck.

  • FTC cell lines were treated with increasing concentrations of rh-TRAIL with and without Smac mimetics Birinapant (A/B). Changes in cell viability are illustrated linearly in percentage control and stratified according to the FP. While FTC cell line TT2609-C02 was susceptible to rh-TRAIL alone (A), cell line FTC133 proved to be resistant to rh-TRAIL induced apoptosis (B). Smac mimetic treatment alone had no impact on cell viability. Annexin-V/PI staining and FACS analyses of FTC cells demonstrate the changes of annexin positive apoptotic cells after incubation with rh-TRAIL alone (-) or in combination (+) with Smac mimetics Birinapant. Changes in protein expression of cIAP1/2 after treatment with the respective Smac mimetic are illustrated using western blot. GAPDH served as loading control. Blots are cropped to increase clarity. Statistical significance was calculated by two-tailed nonparametric Mann-Whitney test. e. survival = expected survival, sp. survival = specific survival, FP = fractional product; *p < 0.05; **p < 0.01.

    Endocr Relat Cancer, 2018, 25(3):295-308. Birinapant purchased from Selleck.

Purity & Quality Control

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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)
<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 Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
PANC-1 MYfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MUG1NE8zODBxNUCwJI5O NYrHZ5M1OC17NjDo NF3jXGNqdmirYnn0d{Bk\WyuIHfyc5d1cCCrbjDic5RpKHSrbXWgZY5lKGSxc3Wg[IVx\W6mZX70JI1idm6nch?= M2fOTlI3OjV{OU[5
Molm13  NFLpfIRHfW6ldHnvckBCe3OjeR?= MWKyM|IxNzJyMDDuUS=> MYeyOEBp NVTvPIhz\GWlcnXhd4V{KGOLQWCxJIFv\CxidH:gZUBufWOqIHzld5NmeiCneITlcpQtKGOLQWCyMEBidmRiWFnBVEB2dmSncjD2ZZJqd3W|IHPvcoRqfGmxboO= Mn22NlQ2OjZ5OEe=
WTH202 MnzjS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWr3boxRPzJiaB?= NVzobY81UUN3ME2xMlghdk1uIHPvcYJqdmWmIIfpeIghOW6pL33sJHRPTi4QsR?= M2CwbFI{PDB|NkO0
WM793B M{HiT2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUjtc4NEPzJiaB?= Ml\BTWM2OD1{LkWgcm0tKGOxbXLpcoVlKHerdHigNY5oN22uIGTOSk3PuQ>? Mm\CNlM1ODN4M{S=
WM9 MoDrS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGDkdoM4OiCq NVnQUJF3UUN3ME2yMlQhdk1? MWiyN|QxOzZ|NB?=
WM9 NI\tToRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MV23NkBp MkS5TWM2OD1{Lkegcm0tKGOxbXLpcoVlKHerdHigNY5oN22uIGTOSk3PuQ>? M3q4ZlI{PDB|NkO0
WM1366 MmHJS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4m4ZVczKGh? M1LLOGlEPTB;Nz65JI5ONCClb33ibY5m\CC5aYToJFFv\y:vbDDUUmYu|rF? NVexZ3NPOjN2MEO2N|Q>
WM164 NUP6cIlbT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3jQ[VczKGh? MUfJR|UxRTlibl2sJINwdWKrbnXkJJdqfGhiMX7nM41tKFSQRj5OtS=> M1jHW|I{PDB|NkO0
451Lu M1jtcWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2DYUFczKGh? MnG1TWM2OD1zND6yJI5ONCClb33ibY5m\CC5aYToJFFv\y:vbDDUUmYu|rF? NVfNV4NLOjN2MEO2N|Q>
WM1341D M3XFbmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHjpXmI4OiCq MmDITWM2OD13Nz62JI5ONCClb33ibY5m\CC5aYToJFFv\y:vbDDUUmYu|rF? MVuyN|QxOzZ|NB?=
WM3130 Mo\lS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWHZZ2JiPzJiaB?= NV7a[mlDUUN3ME22OE4{KG6PLDDjc41jcW6nZDD3bZRpKDGwZz;tcEBVVkZvzsG= NV3RV4RSOjN2MEO2N|Q>
WM1985 MoXKS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{fKS|czKGh? MVfJR|UxRTl5IH7NMEBkd22kaX7l[EB4cXSqIEHu[{9udCCWTl[t{tE> NIPOd3UzOzRyM{[zOC=>
WM3854 MYnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVzjNXVFPzJiaB?= NHfzcIpKSzVyPUKyOkBvVSxiY3;tZolv\WRid3n0bEAydmdxbXygWG5HNc7z M4\JOlI{PDB|NkO0

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
cIAP1 / cIAP2 / XIAP; 

PubMed: 24526787     


Molm13 cells were cultured under standard conditions, standard conditions with mesenchymal stromal cell (MSC) coculture, or hypoxic conditions without or with MSC coculture and treated with birinapant. cIAP1, cellular inhibitor of apoptosis protein-2 (cIAP2), and X-linked inhibitor of apoptosis protein (XIAP) levels were determined by Western blot at 24 hours.

NF-κB(p65) / IκBa / Bcl-xl / NF-κB(p100) / p52; 

PubMed: 24526787     


OCI-AML3 cells were treated with birinapant (bir) for 24 hours. Protein levels in total cell lysates were determined by western blot.

BIRC2 / ARC; 

PubMed: 25079338     


Birinapant treatment decreases BIRC2 and increases ARC protein levels in AML cells and MSCs. OCI-AML3 and Molm13 cells were co-cultured with mesenchymal stem cells (MSCs) and treated with birinapant (bir). Cell lysates from OCI-AML3 and Molm13 cells were collected at 48 and 72 h by combining unattached cells and cells washed off from MSCs; lysates of MSCs were obtained from MSCs co-cultured with Molm13 cells after washing off Molm13 cells. The protein levels were determined by Western blot.

24526787 25079338
Immunofluorescence
Caspase 3/7; 

PubMed: 28665401     


MC38-Ova cells were seeded in chamber slides then overlaid with Pfn−/− OT-I T cells. After 8 h, cells were fixed, stained as indicated, then visualized by confocal microscopy. A minimum of 50 cells was counted in each condition. Error bars represent the mean±S.E.M. of triplicate determinations from a representative experiment, *P<0.05 by unpaired Student's t test.

28665401
Growth inhibition assay
Cell viability; 

PubMed: 28460471     


Cell viability was determined by CCK-8 assay. The data are representative results of three independent experiments.

28460471
In vivo Birinapant (30 mg/kg) treatment significantly induces abrogation of tumor growth in melanoma xenotransplantation models 451Lu with. [2]

Protocol

Kinase Assay:[1]
+ Expand

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 Research:[2]
+ Expand
  • 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
    (Only for Reference)
Animal Research:[2]
+ Expand
  • Animal Models: Human melanoma xenografts 451Lu
  • Formulation: 12.5% Captisol in distilled water
  • Dosages: 30 mg/kg
  • Administration: 3 times per week intraperitoneally
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 100 mg/mL (123.92 mM)
Ethanol 55 mg/mL (68.15 mM)
Water Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
15% Captisol
For best results, use promptly after mixing.
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.

Chemical Information

Molecular Weight 806.94
Formula

C42H56F2N8O6

CAS No. 1260251-31-7
Storage powder
in solvent
Synonyms TL32711

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT03809208 Recruiting Head Cancer|Facial Cancer|Neck Cancer|Upper AerodigestiveTract Cancer|Oral Cancer National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) March 28 2019 Phase 1
NCT03809208 Recruiting Head Cancer|Facial Cancer|Neck Cancer|Upper AerodigestiveTract Cancer|Oral Cancer National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) March 28 2019 Phase 1
NCT03803774 Recruiting Recurrent Head and Neck Squamous Cell Carcinoma National Cancer Institute (NCI) January 7 2019 Phase 1
NCT03803774 Recruiting Recurrent Head and Neck Squamous Cell Carcinoma National Cancer Institute (NCI) January 7 2019 Phase 1
NCT02756130 Withdrawn High Grade Fallopian Tube Serous Adenocarcinoma|High Grade Ovarian Serous Adenocarcinoma|Primary Peritoneal High Grade Serous Adenocarcinoma|Recurrent Fallopian Tube Carcinoma|Recurrent Ovarian Carcinoma|Recurrent Primary Peritoneal Carcinoma Jonsson Comprehensive Cancer Center|National Cancer Institute (NCI) August 1 2018 Phase 1|Phase 2
NCT02756130 Withdrawn High Grade Fallopian Tube Serous Adenocarcinoma|High Grade Ovarian Serous Adenocarcinoma|Primary Peritoneal High Grade Serous Adenocarcinoma|Recurrent Fallopian Tube Carcinoma|Recurrent Ovarian Carcinoma|Recurrent Primary Peritoneal Carcinoma Jonsson Comprehensive Cancer Center|National Cancer Institute (NCI) August 1 2018 Phase 1|Phase 2

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID