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| Targets |
BCL-XL/B-cell lymphoma extra large
Navitoclax-piperazine targets the BCL-2 family of anti-apoptotic proteins, including BCL-2, BCL-xL, and BCL-w. These proteins are key regulators of the intrinsic apoptosis pathway, binding to and inhibiting the pro-apoptotic proteins BAX and BAK. By binding to the hydrophobic groove of BCL-2 and BCL-xL, Navitoclax-piperazine displaces BAX and BAK, allowing them to oligomerize and induce mitochondrial outer membrane permeabilization, leading to apoptosis. The piperazine moiety provides a handle for further conjugation, enabling the development of PROTACs and other targeted therapies. |
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| ln Vitro |
B-cell lymphoma extra large (BCL-XL) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-XL proteolysis-targeting chimera (PROTAC), that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-XL-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets.[1]
In vitro, Navitoclax-piperazine has been shown to potently inhibit the binding of BCL-2 and BCL-xL to pro-apoptotic proteins, with IC₅₀ values in the low nanomolar range. The compound induces apoptosis in cancer cell lines that overexpress BCL-2 or BCL-xL, with EC₅₀ values in the sub-micromolar range. The piperazine moiety does not significantly affect the compound's binding affinity or biological activity, making it a suitable intermediate for further conjugation. |
| ln Vivo |
In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-XL.[1]
In vivo, Navitoclax-piperazine has the potential to demonstrate antitumor efficacy in xenograft mouse models, similar to navitoclax. However, its use as a therapeutic agent may be limited by its thrombocytopenic effects, which are associated with BCL-xL inhibition in platelets. The piperazine moiety allows for the development of conjugates that may have improved pharmacokinetic properties or reduced off-target effects. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for Navitoclax-piperazine involve measuring its binding affinity to BCL-2 and BCL-xL. The assay is typically performed using fluorescence polarization or TR-FRET, where a fluorescently labeled BH3 peptide is used to monitor the binding to the BCL-2 protein. The compound is incubated with the protein and the labeled peptide, and the displacement of the labeled peptide is measured. The IC₅₀ and Ki values are calculated from the displacement curves.
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| Cell Assay |
In vitro cellular experiments for Navitoclax-piperazine are performed using cancer cell lines that overexpress BCL-2 or BCL-xL. Cells are treated with varying concentrations of the compound, and the induction of apoptosis is assessed by measuring caspase activity, Annexin V staining, or mitochondrial membrane potential. Cell viability is assessed using an MTT or CellTiter-Glo assay. The IC₅₀ values are calculated from the concentration-response curves.
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| Animal Protocol |
In vivo animal studies for Navitoclax-piperazine are conducted using immunocompromised mice bearing subcutaneous human tumor xenografts. The compound is administered via oral gavage or intravenous injection at various doses. Tumor volumes and body weights are measured twice weekly to monitor antitumor efficacy and toxicity. At the end of the study, tumors are collected for histopathological analysis and to measure biomarkers of apoptosis.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of Navitoclax-piperazine are expected to be similar to those of navitoclax. The compound is orally bioavailable, with peak plasma concentrations achieved within 2-4 hours. It has a long half-life of approximately 10-20 hours, allowing for once-daily dosing. Navitoclax is extensively metabolized in the liver, primarily by cytochrome P450 enzymes, and its metabolites are excreted via the biliary route.
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| Toxicity/Toxicokinetics |
The toxicity profile of Navitoclax-piperazine is expected to be similar to that of navitoclax. The most significant adverse effect is thrombocytopenia, which is caused by the inhibition of BCL-xL in platelets. Other common adverse effects include gastrointestinal disturbances and fatigue. The compound's safety in humans has been established through clinical trials of navitoclax.
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| References | |
| Additional Infomation |
Navitoclax-piperazine is a derivative of navitoclax with a piperazine moiety that allows for further conjugation. It retains the BCL-2/BCL-xL inhibitory activity of navitoclax and is used in the synthesis of PROTACs and other conjugates targeting the BCL-2 family. Navitoclax-piperazine is a valuable tool for studying apoptosis and developing targeted protein degraders for cancer therapy.
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| Molecular Formula |
C47H56CLF3N6O5S3
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|---|---|
| Molecular Weight |
973.627957344055
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| Exact Mass |
972.311
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| Elemental Analysis |
C, 57.98; H, 5.80; Cl, 3.64; F, 5.85; N, 8.63; O, 8.22; S, 9.88
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| CAS # |
2143096-93-7
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| Related CAS # |
923564-51-6; 1093851-28-5 (HCl); 2143096-93-7 (Navitoclax-piperazine)
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| PubChem CID |
132020434
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| Appearance |
Typically exists as White to off-white solids
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| LogP |
9.3
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
16
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| Heavy Atom Count |
65
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| Complexity |
1800
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1(CCC(=C(C1)CN2CCN(CC2)C3=CC=C(C=C3)C(=O)NS(=O)(=O)C4=CC(=C(C=C4)N[C@H](CCN5CCNCC5)CSC6=CC=CC=C6)S(=O)(=O)C(F)(F)F)C7=CC=C(C=C7)Cl)C
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| InChi Key |
CRPNZDFOWRFBLZ-KXQOOQHDSA-N
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| InChi Code |
InChI=1S/C47H56ClF3N6O5S3/c1-46(2)20-18-42(34-8-12-37(48)13-9-34)36(31-46)32-56-26-28-57(29-27-56)39-14-10-35(11-15-39)45(58)54-65(61,62)41-16-17-43(44(30-41)64(59,60)47(49,50)51)53-38(19-23-55-24-21-52-22-25-55)33-63-40-6-4-3-5-7-40/h3-17,30,38,52-53H,18-29,31-33H2,1-2H3,(H,54,58)/t38-/m1/s1
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| Chemical Name |
4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-1-phenylsulfanyl-4-piperazin-1-ylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide
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| Synonyms |
Navitoclax-piperazine; 2143096-93-7; (r)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((1-(phenylthio)-4-(piperazin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide; 4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-1-phenylsulfanyl-4-piperazin-1-ylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide; SCHEMBL19475750; CRPNZDFOWRFBLZ-KXQOOQHDSA-N;
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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 |
| 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) |
DMSO : ~125 mg/mL (~128.39 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (2.14 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (2.14 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0271 mL | 5.1354 mL | 10.2708 mL | |
| 5 mM | 0.2054 mL | 1.0271 mL | 2.0542 mL | |
| 10 mM | 0.1027 mL | 0.5135 mL | 1.0271 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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