Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C42H56F2N8O6 |
Molecular Weight | 806.9408 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 8 / 8 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CC[C@H](NC(=O)[C@H](C)NC)C(=O)N1C[C@@H](O)C[C@H]1CC2=C(NC3=CC(F)=CC=C23)C4=C(C[C@@H]5C[C@H](O)CN5C(=O)[C@H](CC)NC(=O)[C@H](C)NC)C6=CC=C(F)C=C6N4
InChI
InChIKey=PKWRMUKBEYJEIX-DXXQBUJASA-N
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
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/27915971Curator's Comment: The description was created based on several sources, including
https://clinicaltrials.gov/ct2/show/NCT01681368 | https://clinicaltrials.gov/ct2/show/NCT01486784 | https://clinicaltrials.gov/ct2/show/NCT02756130 | https://www.ncbi.nlm.nih.gov/pubmed/28337955
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27915971
Curator's Comment: The description was created based on several sources, including
https://clinicaltrials.gov/ct2/show/NCT01681368 | https://clinicaltrials.gov/ct2/show/NCT01486784 | https://clinicaltrials.gov/ct2/show/NCT02756130 | https://www.ncbi.nlm.nih.gov/pubmed/28337955
Birinapant is a parenterally administered bivalent peptidomimetic of the SMAC protein (Second Mitochondria-derived Activator of Caspases) and is therefore known as a SMAC mimetic compound. Birinapant is a particularly potent antagonist of two members of the Inhibitor of Apoptosis Proteins (IAP) family, cIAP-1, and cIAP-2. cIAP-1 and -2 are ubiquitin ligases whose expression can protect cells from apoptosis and cause pro-survival effects of TNF-α and related ligands. When Birinapant binds to cIAP-1 or -2 it causes the protein to ubiquitinate itself, which in turn drives the degradation of the protein. In this way, birinapant suppresses the levels of cIAP-1 and cIAP-2 and therefore switches cell signaling to drive tumor cell apoptosis in the presence of TNF-α. Birinapant has been shown to give rise to sustained and substantial reductions of cIAP1 levels in Peripheral Blood Mononuclear Cells (PBMCs) and tumor tissue. To date, Birinapant has been dosed in approximately 450 patients across 9 studies. The majority of studies was in oncology (one in HBV) and primarily recruited patients with refractory solid tumors & hematological malignancies (dominated by ovarian, colorectal, acute myeloid leukemia and Myelodysplastic syndromes). Overall Birinapant has shown acceptable safety and tolerability for further development in oncology indications. The current plans are to study Birinapant clinically in combination with Keytruda® for the treatment solid tumors and in an Investigator-Initiated study at UCLA for high-grade serous carcinoma (HGSC) in combination with platinum-based chemotherapy.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL3038465 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23225169 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Sample Use Guides
47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle
Route of Administration:
Intravenous
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/28337955
Twelve melanoma cell lines (WM115, Sk-Mel-1, Sk-Mel-5, Malme-3M, MeWo, Sk-Mel-2, WM35, WM3211, WM1366, WM1719C, WM3060 and DSMZ) were used for activity evaluation. Cells were seeded in 96-well plates and treated with birinapant (Active Biochem, NJ, USA) and dacarbazine (Medac GmbH, Germany) using 5x5 concentration-combination matrices, with the concentrations for birinapant ranging from 1 nM to 1 μM and for dacarbazine ranging from 1 μg/ml to 1 mg/ml. Drugs were applied simultaneously. Cells were treated for 24 h or 48 h and subsequently stained with propidium iodide (1.3 μg/ml for 10 min) for cell death measurements.
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C274
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ACTIVE MOIETY