B4653-5mg | BV6 [1001600-56-1] Clinisciences

Background

BV6 is a selective inhibitor of IAP family with IC50 value of 7.2 μM when tested with H460 cells [1].
IAP (inhibitor of apoptosis) is a family protein consists of 8 members and serves as endogenous inhibitors of programmed cell death. Until now, more than 5 human IAPs have been discovered includes XIAP, c-IAP1, c-IAP-2, NAIP, Livin and Survivin. It is reported that IAPs overexpression protects cells against a number of proapoptotic stimuli which enables IAPs play a pivotal role in promoting cancer cell survival [2, 3].
BV6 is an inhibitor of IAP family and often used as an adjuvant to sensitize the cancer cells to radiotherapy or chemotherapy. When tested with H460 NSCLC cells, pre-treatment BV6 sensitized the cells to radiation and increased the apoptosis in a time- and dose- dependent manner via reducing the expression of cIAP1 and XIAP [1]. In hematological THP-1 cells, pre-treatment with BV6 increased the CIK cells killing ability and the same results were achieved in solid malignancy RH30 cells [4]
In BALB/c mice model with transplanted abdominal cavities from donor mouse uterine tissue, intraperitoneally with BV6 repressed the advancement of endometriosis, cell proliferative activity via inhibiting the expression of IAPs [5].
References:
[1].   Li, W., et al., BV6, an IAP antagonist, activates apoptosis and enhances radiosensitization of non-small cell lung carcinoma in vitro. J Thorac Oncol, 2011. 6(11): p. 1801-9.
[2].   Altieri, D.C., Survivin - The inconvenient IAP. Semin Cell Dev Biol, 2015.
[3].   Fulda, S., Smac mimetics as IAP antagonists. Semin Cell Dev Biol, 2014.
[4].   Rettinger, E., et al., SMAC Mimetic BV6 Enables Sensitization of Resistant Tumor Cells but also Affects Cytokine-Induced Killer (CIK) Cells: A Potential Challenge for Combination Therapy. Front Pediatr, 2014. 2: p. 75.
[5].   Uegaki, T., et al., Inhibitor of apoptosis proteins (IAPs) may be effective therapeutic targets for treating endometriosis. Hum Reprod, 2015. 30(1): p. 149-58.

Product Citation

1. Yugo Fujita, Toshiyuki Yano, et al. "Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy." ESC Heart Fail. 2022 Oct;9(5):3435-3451. PMID: 35851586
2. Shin Murai, Kanako Takakura, et al. "A FRET biosensor, SMART, monitors necroptosis in renal tubular epithelial cells in a cisplatin-induced kidney injury model." Research Square. December 5th, 2022.
3. Manami Semba, Shinji Takamatsu, et al. "Proscillaridin A Sensitizes Human Colon Cancer Cells to TRAIL-Induced Cell Death." Int J Mol Sci. 2022 Jun 23;23(13):6973. PMID: 35805980
4. Cliff J. Luke, Stephanie Markovina, et al. "Lysoptosis is an evolutionarily conserved cell death pathway moderated by intracellular serpins." Commun Biol. 2022 Jan 12;5(1):47. PMID:35022507
5. Tae-Yeon Kim, Ju-Hui Kang, et al. "Down-regulation of pro-necroptotic molecules blunts necroptosis during myogenesis." Biochem Biophys Res Commun. 2021 Jun 11;557:33-39. PMID:33862457
6. Miles MA, Caruso S, et al. "Smac mimetics can provoke lytic cell death that is neither apoptotic nor necroptotic." Apoptosis. 2020;10.1007/s10495-020-01610-8. PMID:32440848
7. Miyake S, Murai S, et al. "Identification of the hallmarks of necroptosis and ferroptosis by transmission electron microscopy." Biochem Biophys Res Commun. 2020;527(3):839-844. PMID:32430176
8. Lei W, Duan R, et al. "The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice." Sci Rep. 2020;10(1):7004. PMID:32332865
9. Abe K, Yano T, et al. "mTORC1 inhibition attenuates necroptosis through RIP1 inhibition-mediated TFEB activation." Biochim Biophys Acta Mol Basis Dis. 2019 Sep 6:165552. PMID:31499159
10. Liu Z, Mar KB, et al. "A NIK-SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-κB." Nature. 2019 Apr;568(7751):249-253. PMID:30894749
11. Rossi A, Pakhomova ON, et al. "Mechanisms and immunogenicity of nsPEF-induced cell death in B16F10 melanoma tumors." Sci Rep. 2019 Jan 23;9(1):431. PMID:30674926
12. In EJ, Lee Y, et al. "Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis." Molecules.2018 Nov 5;23(11). pii: E2884. PMID:30400632
13. Murai S, Yamaguchi Y, et al. "A FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs." Nat Commun. 2018 Oct 26;9(1):4457. PMID:30367066
14. Yue Y, Nabar NR, et al. "SARS-Coronavirus Open Reading Frame-3a drives multimodal necrotic cell death." Cell Death Dis. 2018 Sep 5;9(9):904. PMID:30185776
15. Dionísio PEA, Oliveira SR, et al. "Loss of Microglial Parkin Inhibits Necroptosis and Contributes to Neuroinflammation." Mol Neurobiol. 2018 Aug 3. PMID:30074231
16. Hao Q, Tang H. "Interferon-γ and Smac mimetics synergize to induce apoptosis of lung cancer cells in a TNFα-independent manner." Cancer Cell Int. 2018 Jun 14;18:84. PMID:29946223
17. Borghi A, Haegman M, et al. "The E3 ubiquitin ligases HOIP and cIAP1 are recruited to the TNFR2 signaling complex and mediate TNFR2-induced canonical NF-κB signaling." Biochem Pharmacol. 2018 Jan 31. pii: S0006-2952(18)30039-X. PMID:29378181
18. Welters MJP, Ma W, et al. "Intratumoral HPV16-Specific T Cells Constitute a Type I-Oriented Tumor Microenvironment to Improve Survival in HPV16-Driven Oropharyngeal Cancer." Clin Cancer Res. 2018 Feb 1;24(3):634-647. PMID:29018052
19. Panayotopoulou EG, Müller AK, et al. "Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells."Oncotarget. 2017 Jul 11;8(28):45088-45104. PMID:28187446
20. Shekhar TM, Miles MA, et al."IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα."Oncotarget. 2016 Jun 7;7(23):33866-86. PMID:27129149

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Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	1205.57
Cas No.	1001600-56-1
Formula	C₇₀H₉₆N₁₀O₈
Solubility	≥60.28 mg/mL in DMSO; insoluble in H2O; ≥12.6 mg/mL in EtOH with ultrasonic
Chemical Name	(S,S,2S,2'S)-N,N'-((2S,2'S)-(hexane-1,6-diylbis(azanediyl))bis(3-oxo-1,1-diphenylpropane-3,2-diyl))bis(1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)pyrrolidine-2-carboxamide)
SDF	Download SDF
Canonical SMILES	O=C(CCCCCCCNC([C@@H](NC([C@H]1N(C([C@H](C2CCCCC2)NC([C@H](C)NC)=O)=O)CCC1)=O)CO=C(NCCCCCCNC([C@@H](NC([C@H]1N(C([C@H](C2CCCCC2)NC([C@H](C)NC)=O)=O)CCC1)=O)C(C3=CC=CC=C3)C4=CC=CC=C4)=O)[C@@H](NC([C@H]5N(C([C@H](C6CCCCC6)NC([C@H](C)NC)=O)=O)CCC5)=O)C(C7=CC=
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment [1]:
Cell lines	HCC193 and H460 non-small cell lung cancer (NSCLC) cell lines.
Preparation method	Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37°C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20°C for several months.
Reaction Conditions	37°C
Applications	BV6 reduces the expression of cIAP1 and XIAP in HCC193 and H460 cell lines in a time and dose-dependent manner. BV6 also induces apoptosis in both HCC193 and H460 cell lines. In addition, BV6 prominently promotes the radiosensitivity of both HCC193 and H460 lung cancer cell lines.
Animal experiment [2]:
Animal models	Mouse endometriosis model
Dosage form	Single i.p. injection of BV6 (10 mg/kg) twice weekly.
Applications	BV6 treatment for 4 weeks attenuates the intensity of IAPs expression and lowers the total number of lesions, the average weight and the surface area of lesions as compared with control group. Moreover, BV6 treatment decreases the percentage of Ki67-positive cells in the endometrial gland epithelia or stroma.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: 1. Li W, Li B, Giacalone NJ, Torossian A et al. BV6, an IAP antagonist, activates apoptosis and enhances radiosensitization of non-small cell lung carcinoma in vitro. J Thorac Oncol. 2011 Nov;6(11):1801-9. 2. Uegaki T, Taniguchi F, Nakamura K et al. Inhibitor of apoptosis proteins (IAPs) may be effective therapeutic targets for treating endometriosis. Hum Reprod. 2015 Jan;30(1):149-58.