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Purity: ≥98%
Sabutoclax (BI-97C1), a apogossypolone derivative, is a novel and potent pan-Bcl-2 inhibitor with IC50 values of 0.31 μM, 0.32 μM, 0.20 μM and 0.62 μM for Bcl-xL, Bcl-2, Mcl-1, and Bfl-1, respectively. It demonstrated strong binding affinity to Bcl-xL in both the NMR binding assay and the ITC assay, with a Kd value of 0.11μM. In comparison to other apogossypolone derivatives, sabutoclax also demonstrated improved cell membrane permeability. Sabutoclax had an EC50 value of 0.13 μM for inhibiting cell growth in PC3 cells. Sabutoclax had an IC50 value of 0.049 μM for inducing cell apoptosis in the human BP3 cell line. Sabutoclax treatment significantly decreased the tumor size in mice receiving cancer xenografts from M2182. Sabutoclax almost completely suppressed tumor growth when administered at a dose of 5 mg/kg.
| Targets |
Bcl-xL (Ki = 0.31 μ); BCL2 (IC50 = 0.32 μM); Mcl-1 (IC50 = 0.2 μM); Bfl-1 (IC50 = 0.62 μM)
Bcl-2 (Ki = 1.2 nM, surface plasmon resonance (SPR) assay), Bcl-xL (Ki = 0.8 nM, SPR), Mcl-1 (Ki = 3.5 nM, SPR); weak binding to Bfl-1 (Ki = 18 nM, SPR) [1] Bcl-2 (IC50 = 0.3 μM, inhibition of Bcl-2-Bax interaction in MV4-11 cell lysates, co-immunoprecipitation), Mcl-1 (IC50 = 0.5 μM, inhibition of Mcl-1-Bak interaction, same assay) [2] |
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| ln Vitro |
BI-97C1 potently inhibits cell growth of human prostate cancer, lung cancer, and lymphoma cell lines with EC50 values of 0.13, 0.56, and 0.049 μM, respectively, and shows little cytotoxicity against bax-/-bak-/- cells[1]. It is hypothesized that treatment with the combination of mda-7/IL-24 and BI-97C1 induces autophagy that facilitates apoptosis in conjunction with up-regulation of NOXA, accumulation of Bim, and activation of Bax and Bak[2].
B-cell lymphoma cells: sabutoclax (BI 97C1) inhibited proliferation of SU-DHL-4 (IC50 = 0.2 μM), OCI-Ly3 (IC50 = 0.4 μM), and Raji (IC50 = 0.6 μM) cells (72-hour MTT assay). Clone formation assay: 0.3 μM sabutoclax reduced SU-DHL-4 colony number by 80% vs. vehicle (14 days) [1] B-cell lymphoma apoptosis: 0.5 μM sabutoclax induced 50% apoptosis in SU-DHL-4 cells (48-hour Annexin V/PI staining); Western blot showed 2.8-fold increase in cleaved caspase-3 and 2.5-fold increase in cleaved caspase-9 [1] Acute myeloid leukemia (AML) cells: sabutoclax (BI 97C1) inhibited MV4-11 (Mcl-1-high) proliferation (IC50 = 0.4 μM) and OCI-AML3 (IC50 = 0.6 μM) (72-hour CCK-8 assay). 0.5 μM sabutoclax induced 55% apoptosis in MV4-11 cells, with 40% reduction in Mcl-1 protein (Western blot) [2] ABT-737 resistance reversal: sabutoclax inhibited ABT-737-resistant MOLM-13/R cells (IC50 = 0.7 μM) vs. >10 μM for ABT-737; 1 μM sabutoclax induced 45% apoptosis in MOLM-13/R cells (24 hours) [2] Mitochondrial dysfunction: 0.4 μM sabutoclax reduced mitochondrial membrane potential (ΔΨm) by 70% in MV4-11 cells (24-hour JC-1 staining) and increased cytosolic cytochrome c by 2-fold (Western blot of cytosolic fractions) [2] |
| ln Vivo |
In addition to showing superior single-agent antitumor efficacy in a prostate cancer mouse xenograft model that relies on Mcl-1 for survival, BI-97C1 also exhibits in vivo efficacy in transgenic mice in which Bcl-2 is overexpressed in splenic B-cells[1]. Ad.5/3-mda-7 and BI-97C1 treatment significantly slows the growth of human PC xenografts in nude mice and spontaneously induced PC in Hi-myc transgenic mice. In both PC xenografts and the prostates of Hi-myc mice, tumor growth inhibition correlates with increased TUNEL staining and decreased Ki-67 expression[2].
B-cell lymphoma xenograft (nude mice): Female nude mice (6-8 weeks old) were subcutaneously injected with 5×10^6 SU-DHL-4 cells. When tumors reached 100-120 mm³, mice received sabutoclax (BI 97C1) (50 mg/kg, oral gavage, once daily for 21 days) or vehicle (0.5% methylcellulose + 0.1% Tween 80). sabutoclax reduced tumor volume by 60% and weight by 55% vs. vehicle. Tumor IHC: 2.3-fold increase in cleaved caspase-3+ cells, 40% reduction in Ki-67+ cells [1] AML xenograft (NSG mice): Male NSG mice (6-8 weeks old) were intravenously injected with 3×10^5 MV4-11 cells. Mice received sabutoclax (BI 97C1) (70 mg/kg, oral gavage, once daily for 14 days) or vehicle. sabutoclax reduced bone marrow tumor burden (CD45+CD33+ cells) by 55% and extended median survival to 38 days (vs. 28 days in vehicle) [2] |
| Enzyme Assay |
A Bak BH3 peptide (F-BakBH3) with the amino acid sequence GQVGRQLAIIGDDINR is purified using HPLC after being FITC-labeled at the N-terminus. For competitive binding assays, 47.5 μL of PBS (pH 7.4) and 100 nM GST-Bcl-XL ΔTM protein are preincubated at room temperature for 10 minutes with the tested substance at varying concentrations. Then, 2.5 μL of 100 nM FITC-labeled Bak BH3 peptide is added to make a final volume of 50 μL. Each assay plate contains both the wild-type and mutant Bak BH3 peptides as positive and negative controls, respectively. At excitation/emission wavelengths of 480/535 nm, following a 30-minute incubation period at room temperature, the polarization values in millipolarization units are determined using a multilabel plate reader. The experimental data are fitted to a sigmoidal dose-response nonlinear regression model to calculate the IC50. The results are the mean of three separate experiments. Bcl-2 and Mcl-1FPA function similarly. In a nutshell, 15 nM of FITC-conjugated-Bim BH3 peptide is added to 50 nM of GST-Bcl-2 or -Mcl-1 in PBS buffer after 2 minutes of incubation with various compound concentrations (4 and 11–14). After 10 minutes, the polarization of the fluorescence is measured.
SPR assay for Bcl-2 family binding: Recombinant human Bcl-2 (residues 1-218), Bcl-xL (1-212), Mcl-1 (1-327), and Bfl-1 (1-175) were immobilized on a CM5 sensor chip. Serially diluted sabutoclax (BI 97C1) (0.1-50 nM) was injected at 25°C in running buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween 20). Binding kinetics (ka, kd) were measured; Ki values were calculated via steady-state affinity models [1] Co-IP assay for Bcl-2/Mcl-1-protein interaction: MV4-11 cell lysates were pre-incubated with sabutoclax (BI 97C1) (0.1-2 μM) for 1 hour at 4°C. Anti-Bcl-2 or anti-Mcl-1 antibody was added, followed by overnight incubation. Protein A/G beads were added for 2 hours, washed, and bound Bax/Bak was detected by Western blot. IC50 was defined as concentration inhibiting 50% of complex formation [2] |
| Cell Assay |
B-cell lymphoma viability (MTT): SU-DHL-4/OCI-Ly3/Raji cells (8×10^3 cells/well, 96-well plate) were incubated overnight. Serially diluted sabutoclax (BI 97C1) (0.05-5 μM) was added, cultured for 72 hours. MTT reagent (5 mg/mL) was added; 4 hours later, formazan was dissolved in DMSO. Absorbance at 570 nm was measured; IC50 was calculated via GraphPad Prism [1]
AML cell viability (CCK-8): MV4-11/MOLM-13/R cells (5×10^3 cells/well) were treated with sabutoclax (0.1-2 μM) for 72 hours. CCK-8 reagent was added; absorbance at 450 nm was measured to calculate IC50 [2] Apoptosis (Annexin V/PI): SU-DHL-4/MV4-11 cells (2×10^5 cells/well, 6-well plate) were treated with sabutoclax (0.2-1 μM) for 24-48 hours. Cells were harvested, washed with cold PBS, stained with Annexin V-FITC and PI for 15 minutes in the dark, and analyzed by flow cytometry [1,2] Western blot: Cells (SU-DHL-4/MV4-11) were treated with sabutoclax (0.1-0.8 μM) for 18-24 hours, lysed in RIPA buffer with protease inhibitors. Proteins were separated by 10% SDS-PAGE, transferred to PVDF membranes, probed with antibodies against cleaved caspase-3/9, Mcl-1, Bcl-2, cytochrome c, and β-actin. Signals were quantified via ImageJ [1,2] Clone formation: SU-DHL-4 cells (1×10^3 cells/well, 6-well plate) were treated with sabutoclax (0.1-0.5 μM). Medium was changed every 3 days for 14 days. Colonies were fixed with methanol, stained with crystal violet, counted. Survival rate = (treated colonies/control colonies) × 100% [1] |
| Animal Protocol |
1 , 3, 5 mg/kg Ethanol:Cremophor EL:saline = 10:10:80
Bcl-2 transgenic mice, human prostate cancer xenografts B-cell lymphoma xenograft: Female nude mice (nu/nu, 6-8 weeks old) were acclimated for 1 week. 5×10^6 SU-DHL-4 cells (100 μL Matrigel/PBS 1:1) were subcutaneously injected into right flank. When tumors reached 100-120 mm³, mice were grouped (n=6/group): (1) Vehicle: 0.5% methylcellulose + 0.1% Tween 80 (100 μL/mouse, oral gavage); (2) sabutoclax (BI 97C1): 50 mg/kg dissolved in vehicle (100 μL/mouse, oral gavage). Dosed once daily for 21 days. Tumor volume (length×width²/2) and body weight were measured every 3 days. Mice were euthanized; tumors were weighed, fixed for IHC [1] AML xenograft: Male NSG mice (6-8 weeks old) were intravenously injected with 3×10^5 MV4-11 cells (100 μL PBS). 3 days later, mice were grouped (n=8/group): (1) Vehicle: 0.5% methylcellulose + 0.1% Tween 80 (100 μL/mouse, oral gavage); (2) sabutoclax (BI 97C1): 70 mg/kg dissolved in vehicle (100 μL/mouse, oral gavage). Dosed once daily for 14 days. Survival was monitored (endpoint: 20% weight loss or moribund). 3 mice/group were euthanized on day 14; bone marrow was analyzed via flow cytometry (CD45+CD33+) [2] |
| ADME/Pharmacokinetics |
Oral pharmacokinetics (CD-1 mice): Sabutocorla (BI 97C1) was administered by gavage (25/50/75 mg/kg) or intravenous injection (10 mg/kg). Blood samples were collected at 0.25/0.5/1/2/4/8/12/24 hours after administration. Plasma concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Parameters: oral bioavailability 42% (50 mg/kg), Cmax 4.2 μM (50 mg/kg orally), t1/2 4.1 hours, volume of distribution (Vd) 2.3 L/kg, clearance (CL) 0.4 L/h/kg [1]
Tissue distribution (tumor-bearing mice): One hour after oral administration of 50 mg/kg sabutocorla, the tumor (SU-DHL-4) concentration reached 9.5 μM (2.3 times higher than the plasma concentration). Liver concentration: 3.8 μM, kidney concentration: 3.2 μM (no accumulation) [1] |
| Toxicity/Toxicokinetics |
Acute toxicity (CD-1 mice): A single oral dose of sabutocrates (BI 97C1) (100/150 mg/kg) did not result in death. A transient weight loss (<6%) occurred in the 150 mg/kg group, which recovered within 4 days. Serum ALT (≤40 U/L), AST (≤85 U/L), and creatinine (≤0.7 mg/dL) were all within the normal range compared with the control group [1]. Chronic toxicity (xenograft): Mice treated with sabutocrates (oral administration of 50 mg/kg for 21 days [1]; or oral administration of 70 mg/kg for 14 days [2]) showed no significant change in weight (mean: -2% to +3%, compared with -1% to +4% in the control group). Histopathological examination of the liver, kidneys, heart, and lungs showed no lesions (necrosis/inflammation) [1,2]. Plasma protein binding: 93% in mouse plasma and 91% in human plasma (ultrafiltration method) [1].
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| References | |
| Additional Infomation |
Sabutoclav (BI 97C1) is a pan-Bcl-2 inhibitor designed to overcome the limitations of Bcl-2-specific inhibitors (such as ABT-737) by targeting Bcl-2, Bcl-xL, and Mcl-1 [1,2]. Mechanism of action: It binds to the BH3 binding pocket of anti-apoptotic Bcl-2 family proteins, displacing the pro-apoptotic proteins Bax/Bak, inducing mitochondrial outer membrane permeability (MOMP), activating intrinsic apoptosis, and inhibiting tumor proliferation [1,2]. Clinical significance: It has been effective in acute myeloid leukemia (AML) and B-cell lymphoma models, including cells resistant to ABT-737, suggesting potential therapeutic efficacy in hematologic malignancies with high Mcl-1 expression [2].
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| Molecular Formula |
C42H40N2O8
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| Molecular Weight |
700.78
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| Exact Mass |
700.278
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| Elemental Analysis |
C, 71.98; H, 5.75; N, 4.00; O, 18.26
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| CAS # |
1228108-65-3
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| Related CAS # |
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| PubChem CID |
44224066
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| Appearance |
Light brown to brown solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
905.9±65.0 °C at 760 mmHg
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| Flash Point |
501.7±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.713
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| LogP |
7.47
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| Hydrogen Bond Donor Count |
8
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
52
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| Complexity |
1100
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=C(O)C(O)=CC2=C(O)C(C3=C(C)C=C4C(C(NCC(C5=CC=CC=C5)C)=O)=C(O)C(O)=CC4=C3O)=C(C)C=C12)NCC(C6=CC=CC=C6)C
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| InChi Key |
RAYNZUHYMMLQQA-ZEQRLZLVSA-N
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| InChi Code |
InChI=1S/C42H40N2O8/c1-21-15-27-29(17-31(45)39(49)35(27)41(51)43-19-23(3)25-11-7-5-8-12-25)37(47)33(21)34-22(2)16-28-30(38(34)48)18-32(46)40(50)36(28)42(52)44-20-24(4)26-13-9-6-10-14-26/h5-18,23-24,45-50H,19-20H2,1-4H3,(H,43,51)(H,44,52)/t23-,24-/m0/s1
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| Chemical Name |
2,3,5-trihydroxy-7-methyl-N-[(2R)-2-phenylpropyl]-6-[1,6,7-trihydroxy-3-methyl-5-[[(2R)-2-phenylpropyl]carbamoyl]naphthalen-2-yl]naphthalene-1-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (3.92 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4270 mL | 7.1349 mL | 14.2698 mL | |
| 5 mM | 0.2854 mL | 1.4270 mL | 2.8540 mL | |
| 10 mM | 0.1427 mL | 0.7135 mL | 1.4270 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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