Inhibitor of apoptosis (IAP) proteins exert a range of biological activities that promote cancer cell survival and proliferation. X chromosome-linked IAP is a direct inhibitor of caspases, pro-apoptotic executioner proteases, whereas cellular IAP proteins block the assembly of pro-apoptotic protein signalling complexes and mediate the expression of anti-apoptotic molecules[3].
Birinapant is a synthetic small molecule that is both a peptidomimetic of second mitochondrial-derived activator of caspases (SMAC) and inhibitor of IAP family proteins, with potential antineoplastic activity. Birinapant binds with XIAP and cIAP1 with K of 45 and <1 nM, respectively.[4]. Birinapant-mediated activation of cIAP1 resulted in cIAP1 autoubiquitylation and degradation and correlated with inhibition of TNF-mediated NF-κB activation, induction of tumor cell death in vitro, and tumor regression in vivo[5]. Birinapant significantly improved the survival rate of endotoxemic mice (P<0.05) and attenuated LPS-induced liver pathologic damage and inflammatory response. IL-1 and TNF-α levels, and cIAP1 expression in liver resident macrophage (Kupffer cells, KCs) was significantly decreased in the Birinapant group compare with the controlled group[6]. Birinapant, alone or in combination with TNFα or TRAIL, decreased cell density in cell lines, with IC50 s ranging from 0.5 nM to > 1 µM. Birinapant alone or with TNF significantly increased subG0 cell death in different lines[7].
Birinapant/比瑞那帕 细胞实验
Cell Line
Concentration
Treated Time
Description
References
IMR-90
2 μM
24 h
To identify genetic modifiers that enhance senescent cell death
Cell Metab. 2023 Oct 3;35(10):1814-1829.e6.
TNBC PDX tumor cells
1 μM
24 or 48 h
To evaluate the killing effect of Birinapant on TNBC PDX tumor cells, results showed that TNBC PDX tumor cells were sensitive to Birinapant
Cell Death Differ. 2020 Oct;27(10):2768-2780.
MDA-MB-231 cells
1 μM
24 h
To evaluate the killing effect of Birinapant on MDA-MB-231 cells, results showed that MDA-MB-231 cells were sensitive to Birinapant
Cell Death Differ. 2020 Oct;27(10):2768-2780.
MDA-MB-468 cells
1 μM
24 h
To evaluate the killing effect of Birinapant on MDA-MB-468 cells, results showed that MDA-MB-468 cells were sensitive to Birinapant
Cell Death Differ. 2020 Oct;27(10):2768-2780.
IMR-90 normal human lung fibroblasts
2 μM
24 h
Screened for genetic modifiers of cell death, identified 14 hits passing 10% FDR threshold
Cell Metab. 2023 Oct 3;35(10):1814-1829.e6.
PANC-1 cells
100 nM
0, 6, 24, 48, 72 h
To investigate the effects of Birinapant in combination with gemcitabine on pancreatic cancer cells, the results showed synergistic effects involving cell cycle regulation and apoptosis signaling pathways.
Front Pharmacol. 2018 Feb 19;9:84.
MDA-MB-468
4 μM
48 h
Birinapant significantly enhanced the immunotoxin-mediated killing of MDA-MB-468 cells, reducing the IC50 by 10-fold to 100-fold.
FASEB J. 2023 Dec;37(12):e23292.
A431
4 μM
48 h
Birinapant only modestly enhanced the immunotoxin-mediated killing of A431 cells, reducing the IC50 by only 5-fold.
FASEB J. 2023 Dec;37(12):e23292.
HT-29 cells
1 µM
4 h
Beclin 1-depleted HT-29 cells were more sensitive to TNF α-induced necroptosis
Cell Death Differ. 2020 Nov;27(11):3065-3081.
Molm-13 cells
0.05 µM
10 h
Beclin 1-depleted Molm-13 cells were more sensitive to Smac mimetic and caspase inhibitor-induced necroptosis
Cell Death Differ. 2020 Nov;27(11):3065-3081.
NALM6 leukemia cells
50 nM
16 to 30 h
To evaluate the effect of Birinapant and TNF combination on inducing extrinsic apoptosis in NALM6 leukemia cells, observing activation of caspase-8 and -9, and cleavage of effector caspase-3, -7, and -6.
Sci Adv. 2019 Jul 31;5(7):eaau9433.
Jurkat leukemia cells
50 nM
To evaluate the effect of Birinapant and TNF combination on inducing extrinsic apoptosis in Jurkat leukemia cells, finding that cells lacking caspase-3 and -7 were resistant to ABT263 but remained sensitive to Birinapant and TNF-induced apoptosis.
Sci Adv. 2019 Jul 31;5(7):eaau9433.
B16F10 cells
1, 5, 10, 20 μM
48 h
To test the effect of Birinapant on MHC-I and PD-L1 expression, results showed that Birinapant specifically upregulated MHC-I with minimal effect on PD-L1.
Cancer Discov. 2021 Jun;11(6):1524-1541.
CT26 cells
1, 5, 10, 20 μM
48 h
To test the effect of Birinapant on MHC-I and PD-L1 expression, results showed that Birinapant specifically upregulated MHC-I with minimal effect on PD-L1.
Cancer Discov. 2021 Jun;11(6):1524-1541.
Birinapant/比瑞那帕 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
CT-2A brain tumour model
Intraperitoneal injection
30 mg/kg
Birinapant in combination with anti-PD-1 antibody significantly extended the survival of mice bearing intracranial CT-2A tumours.
Nat Commun. 2017 Feb 15;8:14278
Mice
Bleomycin-induced pulmonary fibrosis model
Intraperitoneal injection
15 mg/kg
5 days
To evaluate the effect of the ABT-199 and birinapant combination in clearing senescent cells in vivo
Cell Metab. 2023 Oct 3;35(10):1814-1829.e6.
Mice
TNBC PDX models
Intraperitoneal injection
30 mg/kg
Three times per week for seven weeks
To evaluate the in vivo efficacy of Birinapant in TNBC PDX models, results showed that Birinapant significantly attenuated the growth of TNBC PDX models
Cell Death Differ. 2020 Oct;27(10):2768-2780.
Mice
Bleomycin-induced pulmonary fibrosis model
Intraperitoneal injection
15 mg/kg
Once daily for 5 days
Evaluated the effect of ABT-199 and birinapant combination therapy on senescent cell markers in a pulmonary fibrosis model, showing significant reduction in p16INK4a, Il6, Col1a2, and SA-βgal expression
Cell Metab. 2023 Oct 3;35(10):1814-1829.e6.
Nude mice
MDA-MB-468 and A431 tumor xenograft models
Intraperitoneal injection
30 mg/kg
Once daily for 22 days
Combination therapy with birinapant and immunotoxin significantly inhibited the growth of MDA-MB-468 tumors, with complete regression in four out of five mice and 100% overall survival.
FASEB J. 2023 Dec;37(12):e23292.
BALB/c nude mice
Molm-13 cell xenograft model
Intraperitoneal injection
2 mg/kg
Every two days for two weeks
Beclin 1-depleted Molm-13 cells were more sensitive to birinapant and emricasan-induced necroptosis, leading to significant reduction in tumor growth
Cell Death Differ. 2020 Nov;27(11):3065-3081.
Mice
B16F10 melanoma model
Intraperitoneal injection
600 μg/mouse
Every 3 days for a total of 3 times
To test the effect of Birinapant in combination with ICB treatment, results showed that Birinapant alone reduced tumor growth, and further reduced tumor progression when combined with ICB.
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