| Size | Price | |
|---|---|---|
| 100mg | ||
| 250mg | ||
| 500mg | ||
| Other Sizes |
| Targets |
Bcl2
|
|---|---|
| ln Vitro |
BGB-11417 showed superior in vitro activity than venetoclax on the inhibition of both WT Bcl-2 and the G101V mutant, as well as other mutations, with better selectivity over Bcl-xL [1].
|
| ln Vivo |
Sonrotoclax (compound 1) shows anticancer action and reduces tumor growth in female NCG mice with acute lymphoblastic leukemia (ALL) xenografts. It is administered po once daily for 42 days [1].
|
| Enzyme Assay |
Biochemical Competitive Binding Assay [1]
The disruption of the Bcl-2:BAK complex was tested at room temperature using TR-FRET methodology. Compounds (0–1 μM) were preincubated with His-tagged Bcl-2 or Bcl-2 G101V protein for 30 min. The BAK-derived peptide (Ac-GQVGRQLAIIGDK (FITC) INR-amide) and the detection reagents were then added to plates and incubated for another 60 min. The TR-FRET signals (excitation at 337 nm, emission at 490 nm/520 nm) were recorded on the BMG PHERAstar FSX reader, and the IC50 of each compound was determined by fitting the inhibition percentage of the protein–ligand interaction at different compound concentrations using the four-parameter logistic model in Dotmatics. Similar methods were used for Bcl-xL with the exception that the compound concentrations ranged from 0 to 10 μM.[1] Surface Plasmon Resonance (SPR)[1] The binding kinetics of BGB-11417 and venetoclax were measured in an SPR assay using Biacore 8K at room temperature. The experiments were performed in an HBS-N buffer containing 10 mM HEPES pH 7.4, 250 mM NaCl, 50 μM EDTA, 0.1% tween 20, and 1% DMSO. Briefly, His-tagged Bcl-2 (1.33 μg/mL) or His-tagged Bcl-2 G101V (1.56 μg/mL) was captured using an NTA sensor chip (Cytiva, Marlborough, MA). BGB-11417 (0–40 nM) or venetoclax (0–800 nM) was flowed over the chip with 240-s injections and 800-s dissociations at a flow rate of 50 μL/min. The binding KD (equilibrium binding constant) was best fitted using a 1:1 binding site kinetic model. |
| Cell Assay |
Cell Viability Assay [1]
RS4;11 and MOLT-4 were obtained from ATCC (Manassas, VA). RS4;11 and MOLT-4 cells were grown in RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum and 1% penicillin–streptomycin. RS4;11 overexpressing different Bcl-2 mutants were generated by lenti-vectors transduction. In brief, the coding sequences (CDS) of different Bcl-2 mutants were inserted into pWPI plasmid. Transfection of the plasmid together with lentivirus packing plasmids pMD2.G and psPAX2 was performed on HEK293T cells. The culture medium containing virus was collected and used to infect RS4;11 cells, and GFP expressing cells were enriched by FACS. The growth inhibitory activities of compounds were measured using CellTiter-Glo luminescent cell viability assays. Cells were treated with stepwise increasing concentrations of compounds for 2 days. An equal volume of CellTiter-Glo reagent was added to the cell culture medium in each well, and the solution was mixed on an orbital shaker for 2 min to allow cell lysis. The samples were incubated for 10 min to generate stabilized luminescent signal applied to quantify the amount of ATP and thus determine the number of metabolically active cells. The luminescent signal was measured on the PHERAstar FSX reader. The IC50’s of compounds were determined by fitting the cell viability inhibition at different compound concentrations using the four-parameter logistic model in GraphPad Prism software. |
| Animal Protocol |
Animal/Disease Models: Female NCG mice with acute lymphoblastic leukemia (ALL) xenografts[1]
Doses: 5, 15, 50 mg/kg Route of Administration: oral administration; daily , for 42 days Experimental Results: Inhibited tumor growth in a dose-dependent manner.[1] RS4;11 Tumor Xenografts[1] RS4;11 tumor cells (1 × 107/mouse) were implanted sc in the right flanks of the female NCG mice purchased from GemPharmatech Co., Ltd. When tumors reached approximately 170 mm3 in the efficacy study or 650 mm3 in the PD/PK study (on day 11 and day 24 after inoculation, respectively), the mice were randomly divided into indicated groups (n = 10 per group for efficacy and n = 4 per group for PD/PK) based on tumor volume and body weight and treated with compounds for indicated days. All compounds were formulated for oral dosing in 60% (v/v) Phosal 50 PG, 30% (v/v) PEG-400, and 10% (v/v) ethyl alcohol. Mice were treated once or once daily (qd) via oral gavage (po) at 10 mL/kg with the doses. Tumor volume was measured twice weekly in two dimensions using a caliper. Body weights were recorded twice weekly. Mice were monitored daily for clinical signs of toxicity throughout the study.[1] PD/PK Study[1] At indicated time points after single dosing of compounds, blood and tumors were removed and immediately snap-frozen. Total proteins were extracted from the tumors and subjected to ELISA detection of tumor cleaved caspase-3 (Ser 29) levels performed according to the instruction of the human caspase-3 (Ser 29) simple step ELISA kit. For the PK study. Plasma was collected by centrifuge at 5600 rpm for 7 min. The tumor samples were processed by adding ice-cold 50% methanol/water solution to the precut and chopped tumor tissue and then homogenized by an MP FastPrep-24 tissue homogenizer. The proteins in plasma and tumor samples were precipitated using acetonitrile containing an internal standard and then removed by centrifugation at 13 000 rpm for 8 min. The compound levels in plasma and tumor were determined by LC–MS/MS. |
| References |
[1]. J. Med. Chem. 2024. doi.org/10.1021/acs.jmedchem.4c00027.
[2]. Nan HU, et, al. Methods of cancer treatment using bcl-2 inhibitor. WO2021110102A1. |
| Molecular Formula |
C49H59N7O7S
|
|---|---|
| Molecular Weight |
890.10
|
| Exact Mass |
889.42
|
| Elemental Analysis |
C, 66.12; H, 6.68; N, 11.02; O, 12.58; S, 3.60
|
| CAS # |
2383086-06-2
|
| Appearance |
Light yellow to yellow solid
|
| LogP |
9.1
|
| tPSA |
194Ų
|
| SMILES |
C(NS(C1=CC=C(NC[C@@H]2CC[C@@](O)(C)CC2)C([N+]([O-])=O)=C1)(=O)=O)(=O)C1=CC=C(N2CCC3(CC(N4CCC[C@H]4C4=CC=CC=C4C(C)C)C3)CC2)C=C1OC1=CN=C2NC=CC2=C1
|
| InChi Key |
ZQTKOYMWCCSKON-XKXNWSITSA-N
|
| InChi Code |
InChI=1S/C49H59N7O7S/c1-32(2)39-7-4-5-8-40(39)43-9-6-22-55(43)36-28-49(29-36)19-23-54(24-20-49)35-10-12-41(45(26-35)63-37-25-34-16-21-50-46(34)52-31-37)47(57)53-64(61,62)38-11-13-42(44(27-38)56(59)60)51-30-33-14-17-48(3,58)18-15-33/h4-5,7-8,10-13,16,21,25-27,31-33,36,43,51,58H,6,9,14-15,17-20,22-24,28-30H2,1-3H3,(H,50,52)(H,53,57)/t33-,43-,48-/m0/s1
|
| Chemical Name |
N-[4-({[(1r,4r)-4-hydroxy-4-methylcyclohexyl]methyl}amino)-3-nitrobenzene-1-sulfonyl]-4-(2-{(2S)-2-[2-(propan-2-yl)phenyl]pyrrolidin- 1-yl}-7-azaspiro[3.5]nonan-7-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide
|
| Synonyms |
BGB11417; BGB-11417; BGB 11417
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO: ~100 mg/mL (112.35 mM)
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1235 mL | 5.6173 mL | 11.2347 mL | |
| 5 mM | 0.2247 mL | 1.1235 mL | 2.2469 mL | |
| 10 mM | 0.1123 mL | 0.5617 mL | 1.1235 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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