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Purity: ≥98%
Birinapant (TL32711; TL-32711; TL 32711) is a novel and potent bivalent peptidomimetic of the IAP (Inhibitor of Apoptosis Protein) family protein and the second mitochondrial-derived activator of caspases. It might be effective against cancer. A SMAC mimetic antagonist, birinapant primarily inhibits cIAP1 with a Kd of <1 nM in a cell-free assay and is less effective against XIAP.
| Targets |
XIAP (Kd = 45 nM); cIAP1 (Kd <1 nM)
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| ln Vitro |
Birinapant binds to both cIAP1 and XIAP with Kd values of 45 and 1 nM, respectively. Birinapant significantly increases the potency of TNF-α-induced apoptosis in SUM149 (triple-negative, EGFR-activated) cells, which are TRAIL-sensitive but TRAIL-insensitive SUM190 (ErbB2-overexpressing) cells. Rapid cIAP1 degradation, activation of caspases, cleavage of PARP, and activation of NF-B are all brought about by birinapant.[1] In vitro, birinapant and TNF- exhibit an effective antimelanoma effect. While neither substance is effective alone, birinapant combined with TNF-(1 ng/mL) inhibits the growth of the human melanoma cell lines WTH202, WM793B, WM1366, and WM164 with IC50s of 1.8, 2.5, 7.9, and 9 nM, respectively. With an IC50 of 2.4 nM, birinapant alone inhibits the proliferation of WM9 cells. In these cell lines, birinapant significantly inhibits the target proteins cIAP1 and cIAP2.[2]
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| ln Vivo |
Birinapant (30 mg/kg) treatment significantly induces abrogation of tumor growth in melanoma xenotransplantation models 451Lu with. [2]
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| Enzyme Assay |
A fluorogenic substrate is used to ascertain the binding affinities of substances to XIAP and cIAP1, and the Kd values are then reported. The fluorescently labeled modified Smac peptide (AbuRPF-K(5-Fam)-NH2; FP pep-tide) dissociation constant (Kd) is first calculated by titrating varying protein concentrations (0.075–5 μM in half log dilutions) with a fixed concentration of peptide (5 nM). With 5 nM of FP peptide and 50 nM of XIAP used in the assay, the nonlinear least squares fit to a single-site binding model using GraphPad Prism produced the dose-response curves. The FP peptide:protein binary complex is mixed with various concentrations of Smac mimetics (100-0.001 μM in half log dilutions) for 15 min at room temperature in 100 mL of 0.1 M potassium phosphate buffer, pH 7.5, containing 100 mg/mL bovine c-globulin. After incubation, the polarization values are determined using a 520 nm emission filter and a 485 nm excitation filter on a multi-label plate reader.
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| Cell Assay |
After 24 hours of cell attachment, the cells are incubated with birinapant and/or TNF- for another 24 or 72 hours. The MTS assay is then carried out.
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| Animal Protocol |
Human melanoma xenografts 451Lu
30 mg/kg 3 times per week intraperitoneally |
| References |
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| Additional Infomation |
Birinapant is a dipeptide.
Birinapant has been investigated for the treatment of Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukemia (CMML). Birinapant is a synthetic small molecule that is both a peptidomimetic of second mitochondrial-derived activator of caspases (SMAC) and inhibitor of IAP (Inhibitor of Apoptosis Protein) family proteins, with potential antineoplastic activity. As a SMAC mimetic and IAP antagonist, birinapant selectively binds to and inhibits the activity of IAPs, such as X chromosome-linked IAP (XIAP) and cellular IAPs 1 (cIAP1) and 2 (cIAP2), with a greater effect on cIAP1 than cIAP2. Since IAPs shield cancer cells from the apoptosis process, this agent may restore and promote the induction of apoptosis through apoptotic signaling pathways in cancer cells and inactivate the nuclear factor-kappa B (NF-kB)-mediated survival pathway. IAPs are overexpressed by many cancer cell types. They are able to suppress apoptosis by binding to, via their baculoviral lAP repeat (BIR) domains, and inhibiting active caspases-3, -7 and -9. IAP overexpression promotes both cancer cell survival and chemotherapy resistance. |
| Molecular Formula |
C42H56F2N8O6
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|---|---|---|
| Molecular Weight |
806.94
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| Exact Mass |
806.42909
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| Elemental Analysis |
C, 62.51; H, 6.99; F, 4.71; N, 13.89; O, 11.90
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| CAS # |
1260251-31-7
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| Related CAS # |
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| PubChem CID |
49836020
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| Appearance |
white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
1090.5±65.0 °C at 760 mmHg
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| Flash Point |
613.3±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.628
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| LogP |
2.98
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| Hydrogen Bond Donor Count |
8
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
15
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| Heavy Atom Count |
58
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| Complexity |
1350
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| Defined Atom Stereocenter Count |
8
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| SMILES |
FC1C([H])=C([H])C2=C(C=1[H])N([H])C(C1=C(C3C([H])=C([H])C(=C([H])C=3N1[H])F)C([H])([H])[C@]1([H])C([H])([H])[C@@]([H])(C([H])([H])N1C([C@]([H])(C([H])([H])C([H])([H])[H])N([H])C([C@]([H])(C([H])([H])[H])N([H])C([H])([H])[H])=O)=O)O[H])=C2C([H])([H])[C@]1([H])C([H])([H])[C@@]([H])(C([H])([H])N1C([C@]([H])(C([H])([H])C([H])([H])[H])N([H])C([C@]([H])(C([H])([H])[H])N([H])C([H])([H])[H])=O)=O)O[H]
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| InChi Key |
PKWRMUKBEYJEIX-DXXQBUJASA-N
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| InChi Code |
InChI=1S/C42H56F2N8O6/c1-7-33(49-39(55)21(3)45-5)41(57)51-19-27(53)15-25(51)17-31-29-11-9-23(43)13-35(29)47-37(31)38-32(30-12-10-24(44)14-36(30)48-38)18-26-16-28(54)20-52(26)42(58)34(8-2)50-40(56)22(4)46-6/h9-14,21-22,25-28,33-34,45-48,53-54H,7-8,15-20H2,1-6H3,(H,49,55)(H,50,56)/t21-,22-,25-,26-,27-,28-,33-,34-/m0/s1
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| Chemical Name |
(2S)-N-[(2S)-1-[(2R,4S)-2-[[6-fluoro-2-[6-fluoro-3-[[(2R,4S)-4-hydroxy-1-[(2S)-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]pyrrolidin-2-yl]methyl]-1H-indol-2-yl]-1H-indol-3-yl]methyl]-4-hydroxypyrrolidin-1-yl]-1-oxobutan-2-yl]-2-(methylamino)propanamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (2.58 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (2.58 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (2.58 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 15% Captisol: 15mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2392 mL | 6.1962 mL | 12.3925 mL | |
| 5 mM | 0.2478 mL | 1.2392 mL | 2.4785 mL | |
| 10 mM | 0.1239 mL | 0.6196 mL | 1.2392 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01940172 | Completed | Drug: Birinapant Drug: Conatumumab |
Relapsed Fallopian Tube Cancer Relapsed Epithelial Ovarian Cancer |
Memorial Sloan Kettering Cancer Center |
November 2013 | Phase 1 |
| NCT01828346 | Completed | Drug: Birinapant Drug: 5-Azacitidine |
Myelodysplastic Syndrome | TetraLogic Pharmaceuticals | June 2013 | Phase 1 Phase 2 |
| NCT01188499 | Completed | Drug: Birinapant | Cancer | TetraLogic Pharmaceuticals | October 2010 | Phase 1 Phase 2 |
| NCT00993239 | Completed | Drug: Birinapant (TL32711) |
Cancer | TetraLogic Pharmaceuticals | November 2009 | Phase 1 |
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