Birinapant

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WARNING: This product is for research use only, not for human or veterinary use.

Description:Birinapant, also known as TL32711, is a synthetic small molecule and peptido mimetic 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, TL32711 binds to and inhibits the activity of IAPs, such as X chromosome-linked IAP (XIAP) and cellular IAPs 1 and 2.

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Chemical Structure

Theoretical Analysis

MedKoo Cat#: 205645Name: BirinapantCAS#: 1260251-31-7Chemical Formula: C42H56F2N8O6Exact Mass: 806.42909Molecular Weight: 806.94Elemental Analysis:C, 62.51; H, 6.99; F, 4.71; N, 13.89; O, 11.90

Synonym:TL32711; TL-32711; TL 32711; SMAC mimetic; Birinapant

IUPAC/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

InChi Key:PKWRMUKBEYJEIX-DXXQBUJASA-N

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

SMILES Code:C[C@H](NC)C(N[C@@H](CC)C(N1[C@H](CC2=C(C(N3)=C(C[C@H]4N(C([C@@H](NC([C@@H](NC)C)=O)CC)=O)C[C@@H](O)C4)C5=C3C=C(F)C=C5)NC6=C2C=CC(F)=C6)C[C@H](O)C1)=O)=O

Technical Data

Additional Information

In Phase 1 clinical studies as a single agent and in combination with standard-of-care chemotherapies, TL32711 has demonstrated strong correlation between drug exposure, target coverage and apoptosis induction in tumors at well-tolerated doses as well as promising anti-tumor activity in patients. TL32711 is entering Phase 2 single agent and combination clinical studies in solid tumors and a Phase 1/2 clinical study in acute myeloid leukemia. TetraLogic will execute a Phase 2 clinical program to explore the broad therapeutic potential of Smac mimetics with the support of substantial non-dilutive funding that reduces downstream equity requirements. (source: http://www.tetralogicpharma.com/research_tl32711.html).    

References

1: Elsawy MA, Tikhonova IG, Martin SL, Walker B. Smac-derived Aza-peptide As an Aminopeptidase-resistant XIAP BIR3 Antagonist. Protein Pept Lett. 2015 Jun 21. [Epub ahead of print] PubMed PMID: 26095377.

2: Ebert G, Allison C, Preston S, Cooney J, Toe JG, Stutz MD, Ojaimi S, Baschuk N, Nachbur U, Torresi J, Silke J, Begley CG, Pellegrini M. Eliminating hepatitisB by antagonizing cellular inhibitors of apoptosis. Proc Natl Acad Sci U S A. 2015 May 5;112(18):5803-8. doi: 10.1073/pnas.1502400112. Epub 2015 Apr 20. PubMed PMID: 25902530; PubMed Central PMCID: PMC4426438.

3: Papaevangelou E, Almeida GS, Jamin Y, Robinson SP, deSouza NM. Diffusion-weighted MRI for imaging cell death after cytotoxic or apoptosis-inducing therapy. Br J Cancer. 2015 Apr 28;112(9):1471-9. doi: 10.1038/bjc.2015.134. Epub 2015 Apr 16. PubMed PMID: 25880014; PubMed Central PMCID: PMC4453679.

4: Brady SW, Zhang J, Tsai MH, Yu D. PI3K-independent mTOR activation promotes lapatinib resistance and IAP expression that can be effectively reversed by mTORand Hsp90 inhibition. Cancer Biol Ther. 2015;16(3):402-11. doi: 10.1080/15384047.2014.1002693. PubMed PMID: 25692408.

5: Lee EW, Seong D, Seo J, Jeong M, Lee HK, Song J. USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics.Cell Death Differ. 2015 Jan 23. doi: 10.1038/cdd.2014.234. [Epub ahead of print]PubMed PMID: 25613375.

6: Eytan DF, Snow GE, Carlson SG, Schiltz S, Chen Z, Van Waes C. Combination effects of SMAC mimetic birinapant with TNFα, TRAIL, and docetaxel in preclinical models of HNSCC. Laryngoscope. 2015 Mar;125(3):E118-24. doi: 10.1002/lary.25056.Epub 2014 Nov 28. PubMed PMID: 25431358; PubMed Central PMCID: PMC4336212.

7: Mak PY, Mak DH, Ruvolo V, Jacamo R, Kornblau SM, Kantarjian H, Andreeff M, Carter BZ. Apoptosis repressor with caspase recruitment domain modulates second mitochondrial-derived activator of caspases mimetic-induced cell death through BIRC2/MAP3K14 signalling in acute myeloid leukaemia. Br J Haematol. 2014 Nov;167(3):376-84. doi: 10.1111/bjh.13054. Epub 2014 Jul 31. PubMed PMID: 25079338; PubMed Central PMCID: PMC4357400.

8: Condon SM, Mitsuuchi Y, Deng Y, LaPorte MG, Rippin SR, Haimowitz T, AlexanderMD, Kumar PT, Hendi MS, Lee YH, Benetatos CA, Yu G, Kapoor GS, Neiman E, Seipel ME, Burns JM, Graham MA, McKinlay MA, Li X, Wang J, Shi Y, Feltham R, Bettjeman B, Cumming MH, Vince JE, Khan N, Silke J, Day CL, Chunduru SK. Birinapant, a smac-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies. J Med Chem. 2014 May 8;57(9):3666-77. doi: 10.1021/jm500176w. Epub 2014 Apr 15. PubMed PMID: 24684347.

9: Benetatos CA, Mitsuuchi Y, Burns JM, Neiman EM, Condon SM, Yu G, Seipel ME, Kapoor GS, Laporte MG, Rippin SR, Deng Y, Hendi MS, Tirunahari PK, Lee YH, Haimowitz T, Alexander MD, Graham MA, Weng D, Shi Y, McKinlay MA, Chunduru SK. Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-κB activation, and is active in patient-derived xenograft models. Mol Cancer Ther. 2014 Apr;13(4):867-79. doi: 10.1158/1535-7163.MCT-13-0798. Epub 2014 Feb 21. Erratum in: Mol Cancer Ther. 2014 Sep;13(9):2246-7. Dosage error in article text. PubMed PMID: 24563541.

10: Carter BZ, Mak PY, Mak DH, Shi Y, Qiu Y, Bogenberger JM, Mu H, Tibes R, Yao H, Coombes KR, Jacamo RO, McQueen T, Kornblau SM, Andreeff M. Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents. J Natl Cancer Inst. 2014 Feb;106(2):djt440. doi: 10.1093/jnci/djt440. PubMed PMID: 24526787; PubMed Central PMCID: PMC3952202.