(R)-(-)-Gossypol (AT-101) acetic acid

製品コードS2812 バッチS281202

印刷

化学情報

Chemical Structure Synonyms Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C30H30O8.C2H4O2
分子量 578.61 CAS No. 866541-93-7
Solubility (25°C)* 体外 DMSO 100 mg/mL (172.82 mM)
Ethanol 100 mg/mL (172.82 mM)
Water Insoluble
体内 （毎回新しく調製した物を用意してください）
Clear solution
2%DMSO 30%PEG300 2%Tween80 66%ddH2O
4.0mg/ml Taking the 1 mL working solution as an example, add 20 μL of 200 mg/ml clarified DMSO stock solution to 300 μL of PEG300, mix evenly to clarify it; add 20 μL of Tween80 to the above system, mix evenly to clarify; then continue to add 660 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results. 
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 (R)-(-)-Gossypol (AT-101) acetic acid, the R-(-) enantiomer of Gossypol acetic acid, binds with Bcl-2, Bcl-xL and Mcl-1 with Ki of 0.32 μM, 0.48 μM and 0.18 μM in cell-free assays; does not inhibit BIR3 domain and BID. AT-101 simultaneously triggers apoptosis and a cytoprotective type of autophagy. Phase 2.
in vitro AT-101 inhibits a panel of different lymphoproliferative malignancies with IC50 ranged from 1.2 μM to 7.4 μM. AT-101 (10 μM) disrupts the Δψm in a concentration- and time-dependent manner in a diffuse large B-cell and in mantle cell lymphoma lines. AT-101 (1 μM or 2 μM) combined with carfilzomib (6 nM or 10 nM) induces apoptosis in HBL-2 and Granta cell lines. [2] AT-101 (20 μM for 24 hours) results in a median 72% apoptosis and down-regulation of Mcl-1 in CLL lymphocytes in both suspension culture as well as stromal coculture. Stromal cells express undetectable levels of antiapoptotic but high levels of activated ERK and AKT proteins and has low or no apoptosis with AT-101. [3] AT-101 induces apoptosis in a time- and dose-dependent fashion, with ED50 values of 1.9 mM and 2.4 mM in Jurkat T and U937 cells, respectively. AT-101 (10 μM) combined with radiation (32 Gy) induces more apoptosis than radiation alone and exceeds the sum of the effects caused by the single agent treatments. AT-101 activates SAPK/JNK in a dose- and time-dependent manner. [4] AT-101 (10 µM) induces apoptosis through activation of caspase-9, -3, and -7 in VCaP Cells. AT-101 (10 µM) decreases Bcl-2 and Mcl-1 expression in VCaP cells. [5] AT-101 (< 20 μM) is able to inhibit the growth of multiple myeloma cells despite the stimulatory growth effects provided by stromal cells in the bone marrow milieu. AT-101 (10 μM) induces apoptosis in multiple myeloma cells via the activation of caspases 3, caspases 9 and PARP. AT-101 (10 μM) promotes apoptosis in multiple myeloma cells by disrupting the Bax/Bcl-2 ratio and the mitochondrial membrane potential. [6]
in vivo AT-101 is still detectable in plasma with average concentrations of 0.49 μM for the 35 mg/kg group and 0.39 μM for the 200 mg/kg group in SCID beige mice bearing RL-DLBCL xenograft. AT-101 peak plasma concentration is observed after 30 minutes of administration of the drug in both the dose levels, with the 200 mg/kg group showing a plasma average concentration almost 4 times greater than the 35 mg/kg group (7.88 μM and 27.78 μM respectively) in SCID beige mice. AT-101 (25 mg/kg to 100 mg/kg, orally) indefinitely results in earlier onset of weight loss equivalent to more than 10% of the pretreatment weight and death in SCID beige mice. AT-101 (35 mg/kg, orally per day for 10 days) plus intraperitoneal cyclophosphamide (Cy) and intraperitoneal rituximab (R) show significantitumor volume control compared to any other treatment group. [2] AT-101 (15 mg/kg, p.o., 5 days/week) as a single agent in intact mice significantly reduces the development of VCaP tumor growth compared to untreated tumors at weeks 2 to 6. AT-101 in combination with surgical castration delays the onset of androgen-independent VCaP tumor growth compared to castration-only or AT-101-only groups in mice. [5]

プロトコル(参考用のみ)

キナーゼアッセイ Fluorescence-Polarization-Based Binding Assay
For competitive binding experiments, Bcl-2 protein (40 nM) and FAM-Bid peptide (2.5 nM) are preincubated in the assay buffer (100 mM potassium phosphate, pH 7.5; 100 μg/mL bovine gamma globulin; 0.02% sodium azide, 5 μL of a solution in DMSO of AT101 is added to the Bcl-2/FAM-Bid solution in Dynex 96-well, black, round-bottom plates to produce a final volume of 125 μL. For each experiment, a control containing Bcl-2 and Flu-Bid peptide (equivalent to 0% inhibition), and another control containing only FAM-Bid, are included on eachassay plate. After 4 hours incubation, the polarization values in milipolarization units (mP) weremeasured at an excitation wavelength at 485 nm and an emission wavelength at 530 nm using the Ultra plate reader. IC50,the inhibitor concentration at which 50% of bound peptide is displaced, is determined from the plot using nonlinear leastsquares analysis and curve fitting performed using GraphPad Prizm 4 software. The unlabeled Bid BH3 peptide is used as the positive control. PF for Bcl-xL protein, Bak BH3 peptide labeled with 6-carboxyfluorescein succinimidyl ester (FAM-Bak) instead of the FAM-Bim to maximize the signal. It is determined that FAM-Bak has a Kd of 6 nM to Bcl-xL protein. The competitive binding assay for Bcl-xL is same as that for Bcl-2 with the following exceptions. 30 nM of Bcl-xL protein and 2.5 nM of FAM-Bak peptide in the following assay buffer: 50 mM Tris-Bis, pH 7.4 and 0.01% bovine gamma globulin. PF for Mcl-1 protein, FAM-Bid peptide and human Mcl-1 protein are used. It is determined that FAM-Bid peptide binds to human Mcl-1 protein with a Kd of 1.71 nM. The competitive binding assays for Mcl-1 are performed in the same manner as that for Bcl-2 with the following exceptions. 5 nM Mcl-1 and 1 nM Flu-Bid peptide in the following assay buffer: 25 mM Tris, pH 8.0; 150 mM NaCl and 0.05% Pluronic acid
細胞アッセイ 細胞株 RL, H9, SKI, HBL-2, Granta and JJN-3 cell lines
濃度 ~10 μM
反応時間 72 hours
実験の流れ Cells are counted and resuspended at an approximate concentration of 3×105 cells/well in a 24-well plate. AT-101 is diluted in DMSO that is maintained at a final concentration of less than 0.5%. Concentrations of AT-101 from 1 nM to 10 μM are used in most experiments. Following incubation at 37 ℃ in a 5% CO2 humidified incubator, 100 μL from each well is transferred to a 96-well opaque-walled plate; cell-Titer-Glo Reagent is added in a 1:1 ratio. Contents are mixed for 2 minutes on an orbital shaker to induce cell lysis. The plates are allowed to incubate at room temperature for 10 minutes before recording luminescence with a Synergy HT Multi-Detection Microplate Reader. In the schedule dependency experiments, serial dilutions of each drug are prepared in ratios relative to their IC50. Cells are preincubated with AT-101 for up to 72 hours, while 4-HC is added for a 24-hour period, being added at time 0, 24 hours, and 48 hours from the start of incubation. Each experiment is performed in triplicate and repeated at least twice.
動物実験 動物モデル SCID beige mice bearing RL-DLBCL xenograft
投薬量 100 mg/kg
投与方法 Oral gavage

カスタマーフィードバック

, , Drug Des Devel Ther, 2014, 8:2517-29.

Data from [Data independently produced by , , Oncotarget, 2016, 7(23):34430-41]

Data from [Data independently produced by , , Front Pharmacol, 2018, 9:1269]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation [ Protein Cell, 2024, pwad065] PubMed: 38167949
Pharmacological Targeting of Bcl-2 Induces Caspase 3-Mediated Cleavage of HDAC6 and Regulates the Autophagy Process in Colorectal Cancer [ Int J Mol Sci, 2023, 24(7)6662] PubMed: 37047634
Integrative analysis of drug response and clinical outcome in acute myeloid leukemia [ Cancer Cell, 2022, S1535-6108(22)00312-9] PubMed: 35868306
Lactate Dehydrogenase B Is Required for Pancreatic Cancer Cell Immortalization Through Activation of Telomerase Activity [ Front Oncol, 2022, 12:821620] PubMed: 35669414
AT101 [(-)-Gossypol] Selectively Inhibits MCL1 and Sensitizes Carcinoma to BH3 Mimetics by Inducing and Stabilizing NOXA [ Cancers (Basel), 2020, 12(8):E2298] PubMed: 32824203
Using CETSA assay and a mathematical model to reveal dual Bcl-2/Mcl-1 inhibition and on-target mechanism for ABT-199 and S1. [ Eur J Pharm Sci, 2020, 142:105105] PubMed: 31669390
Comparison of putative BH3 mimetics AT-101, HA14-1, sabutoclax and TW-37 with ABT-737 in platelets. [ Platelets, 2020, 10.1080/09537104.2020.1724276] PubMed: 32079453
Effect of Exosomal APE1 on Sensitivity of NSCLC A549 Cells to Cisplatin [ Cancer Research on Prevention and Treatment, 2020, (7): 492-497] PubMed: None
Alveolar Macrophage Apoptosis-associated Bacterial Killing Helps Prevent Murine Pneumonia. [ Am J Respir Crit Care Med, 2019, 200(1):84-97] PubMed: 30649895
AT‑101 induces G1/G0 phase arrest via the β‑catenin/cyclin D1 signaling pathway in human esophageal cancer cells. [ Oncol Rep, 2019, 41(2):1415-1423] PubMed: 30483745

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