|Numéro de catalogue: GC39355|
BTSA1 est un activateur BAX puissant, de haute affinité et actif par voie orale avec un IC50 de 250 nM et un EC50 de 144 nM. BTSA1 se lie avec une affinité et une spécificité élevées au site d'activation N-terminal et induit des changements conformationnels À BAX conduisant À l'apoptose médiée par BAX.
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BTSA1 is a potent, high affinity and orally active BAX activator with an IC50 of 250 nM and an EC50 of 144 nM. BTSA1 binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis.
. Reyna DE, et al. Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia. Cancer Cell. 2017 Oct 9;32(4):490-505.e10.
|Solubilité||DMSO: 25 mg/mL (58.07 mM)||Storage||Store at -20°C|
|Conseils généraux||Afin d'obtenir une solubilité plus élevée, veuillez chauffer le tube à 37 °C et le secouer dans le bain à ultrasons pendant un certain temps. La solution mère peut être conservée à une température inférieure à -20 °C pendant plusieurs mois.|
|Condition d'expédition||Solution d'échantillon d'évaluation : livré avec la glace bleue
Toute autre taille disponible : livré avec RT ou la glace bleue sur demande
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Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer
Nat Commun 2022 Mar 7;13(1):1199.PMID:35256598DOI:10.1038/s41467-022-28741-7.
Deregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments. Cancer cells commonly evade apoptosis through upregulation of the BCL-2 anti-apoptotic proteins; however, more resistant cancers also downregulate or inactivate pro-apoptotic proteins to suppress apoptosis. Here, we find that apoptosis resistance in a diverse panel of solid and hematological malignancies is mediated by both overexpression of BCL-XL and an unprimed apoptotic state, limiting direct and indirect activation mechanisms of pro-apoptotic BAX. Both survival mechanisms can be overcome by the combination of an orally bioavailable BAX activator, BTSA1.2 with Navitoclax. The combination demonstrates synergistic efficacy in apoptosis-resistant cancer cells, xenografts, and patient-derived tumors while sparing healthy tissues. Additionally, functional assays and genomic markers are identified to predict sensitive tumors to the combination treatment. These findings advance the understanding of apoptosis resistance mechanisms and demonstrate a novel therapeutic strategy for cancer treatment.
Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia
Cancer Cell 2017 Oct 9;32(4):490-505.e10.PMID:29017059DOI:10.1016/j.ccell.2017.09.001.
The BCL-2 family protein BAX is a central mediator of apoptosis. Overexpression of anti-apoptotic BCL-2 proteins contributes to tumor development and resistance to therapy by suppressing BAX and its activators. We report the discovery of BTSA1, a pharmacologically optimized BAX activator that binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis. BTSA1-induced BAX activation effectively promotes apoptosis in leukemia cell lines and patient samples while sparing healthy cells. BAX expression levels and cytosolic conformation regulate sensitivity to BTSA1. BTSA1 potently suppressed human acute myeloid leukemia (AML) xenografts and increased host survival without toxicity. This study provides proof-of-concept for direct BAX activation as a treatment strategy in AML.
Optimization of BAX trigger site activator BTSA1 with improved antitumor potency and in vitro ADMET properties
Eur J Med Chem 2023 Feb 15;248:115076.PMID:36680883DOI:10.1016/j.ejmech.2022.115076.
Direct activation of the pro-apoptotic protein BAX represents a potential therapeutic strategy to trigger apoptosis in cancer. Herein, structural optimization of the reported BAX trigger site activator BTSA1 turned out into a series of pyrazolone derivatives, where compound 6d exhibited significantly enhanced antiproliferative effects and apoptosis induction ability compared to BTSA1. Mechanism of action studies revealed that compound 6d could initiate the BAX activation cascade, promoting BAX insertion into mitochondrial membranes and activating MOMP, ultimately leading to the release of cytochrome c and apoptosis. Furthermore, 6d showed significantly improved in vitro stability and CYPs profile compared to BTSA1. This work may lay a foundation to develop potent BAX trigger site activators for the treatment of BAX-expressing malignancies.
HDAC-Bax Multiple Ligands Enhance Bax-Dependent Apoptosis in HeLa Cells
J Med Chem 2020 Oct 22;63(20):12083-12099.PMID:33021789DOI:10.1021/acs.jmedchem.0c01454.
Inspired by the synergistic effect of BTSA1 (a Bax activator) and SAHA (a histone deacetylase (HDAC) inhibitor) in HeLa cell growth suppression, a series of novel HDAC-Bax multiple ligands were designed rationally. Compound 23, which possesses similar HDAC inhibitory activity relative to SAHA and Bax affinity comparable to BTSA1, exhibits a superior growth suppression against HeLa cells, and its antiproliferative activities are 15-fold and 3-fold higher than BTSA1 and SAHA, respectively. The better antiproliferative activity and lower cytotoxicity of compound 23 indicated that our HDAC-Bax multiple ligand design strategy achieved success. Further studies suggested that compound 23 could enhance Bax-dependent apoptosis by upregulating Bax, followed by inducing the conformational activation of Bax. To our knowledge, we first report HDAC-Bax multiple ligands and demonstrate a new paradigm for the treatment of solid tumors by enhancing Bax-dependent apoptosis.
L-Cystathionine Protects against Homocysteine-Induced Mitochondria-Dependent Apoptosis of Vascular Endothelial Cells
Oxid Med Cell Longev 2019 Nov 25;2019:1253289.PMID:31885769DOI:10.1155/2019/1253289.
The study was aimed at investigating the effects of L-cystathionine on vascular endothelial cell apoptosis and its mechanisms. Cultured human umbilical vein endothelial cells (HUVECs) were used in the study. Apoptosis of vascular endothelial cells was induced by homocysteine. Apoptosis, mitochondrial superoxide anion, mitochondrial membrane potential, mitochondrial permeability transition pore (MPTP) opening, and caspase-9 and caspase-3 activities were examined. Expression of Bax, Bcl-2, and cleaved caspase-3 was tested and BTSA1, a Bax agonist, and HUVEC Bax overexpression was used in the study. Results showed that homocysteine obviously induced the apoptosis of HUVECs, and this effect was significantly attenuated by the pretreatment with L-cystathionine. Furthermore, L-cystathionine decreased the production of mitochondrial superoxide anion and the expression of Bax and restrained its translocation to mitochondria, increased mitochondrial membrane potential, inhibited mitochondrial permeability transition pore (MPTP) opening, suppressed the leakage of cytochrome c from mitochondria into the cytoplasm, and downregulated activities of caspase-9 and caspase-3. However, BTSA1, a Bax agonist, or Bax overexpression successfully abolished the inhibitory effect of L-cystathionine on Hcy-induced MPTP opening, caspase-9 and caspase-3 activation, and HUVEC apoptosis. Taken together, our results indicated that L-cystathionine could protect against homocysteine-induced mitochondria-dependent apoptosis of HUVECs.
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