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Purity: ≥98%
Venetoclax (formerly known as ABT-199 or GDC-0199; Venclexta) is a potent, selective and orally bioavailable small molecule inhibitor of the anti-apoptotic protein BCL-2 (B-cell lymphoma-2) with Ki of<0.01 nM. On April 11, 2016, the FDA authorized venetoclax for use in CLL patients who have a 17p deletion (a deletion on the short arm of chromosome 17) and who have received at least one prior therapy. Venetoclax works as a BCL-2 inhibitor by mimicking BH3, which is the native ligand of BCL-2. It prevents the anti-apoptotic BCL-2 protein, causing CLL cells to undergo programmed cell death.
Venetoclax (brand name Venclexta/Venclyxto) is a first-in-class, orally bioavailable small-molecule inhibitor specifically targeting the anti-apoptotic protein B-cell lymphoma 2 (BCL-2). By selectively binding to BCL-2, it displaces pro-apoptotic proteins (such as BIM), thereby triggering mitochondrial outer membrane permeabilization and restoring programmed cell death in malignant cells. Clinically, venetoclax is approved for chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and acute myeloid leukemia (AML), often in combination with hypomethylating agents or low-dose cytarabine. Its use requires careful tumor lysis syndrome (TLS) risk assessment and dose ramp-up.| Targets |
Bcl-2 (Ki = 0.01 nM); Bcl-xL (Ki = 48 nM); Bcl-W (Ki = 245 nM)
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| ln Vitro |
ABT-199 shows less sensitivity to Bcl-xL, Mcl-1 and Bcl-w with Ki of 48 nM, > 444 nM and 245 nM, respectively. ABT-199 exhibits weak activity against FL5.12-Bcl-xL cells with an EC50 of 261 nM, but potently inhibits FL5.12-Bcl-2 cells, RS4;11 cells with EC50s of 4 nM and 8 nM. In RS4;11 cells, ABT-199 causes a rapid apoptosis that is accompanied by the release of cytochrome c, activation of caspase, externalization of phosphatidylserine, and accumulation of sub-G0/G1 DNA. According to quantitative immunoblotting, Bcl-2 expression was strongly correlated with ABT-199 sensitivity in cell lines from NHL, DLBCL, MCL, AML, and ALL. The average EC50 for ABT-199 inducing apoptosis in CLL is 3.0 nM. [1]
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| ln Vivo |
ABT-199 (100 mg/kg) causes a maximal tumor growth inhibition of 95% and tumor growth delay of 152% in RS4;11 xenografts. ABT-199 can be used alone or in combination with other drugs, such as SDX-105, to inhibit the growth of xenografts (DoHH2, Granta-519). [1]
Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. [2] To address antileukemia activities of VEN in individual leukemia samples in a situation more similar to a potential clinical application, we investigated its antileukemia activities in a preclinical phase-II-like trial on different individual, patient-derived xenograft ALL samples in mice (N = 12). Three weeks after transplantation onto recipient mice, ALL-bearing animals were treated with VEN (Venetoclax) for 10 days and times to reoccurrence of full-blown, clinically apparent leukemia after treatment with VEN or vehicle were compared for each leukemia. We observed distinct in vivo antileukemia activities of VEN (Venetoclax) indicated by differences of survival times (‘delta survival’) ranging from minimal effects to prolonged survival without manifestation of ALL for more than 140 days (Fig. (Fig.3a).3a). This variation of in vivo responses is similar to the heterogeneity of VEN sensitivities observed ex vivo, and EC50 values analyzed ex vivo showed a moderate association with in vivo survival times.[3] Upon leukemia manifestation (presence of 5% human ALL cells in the recipients peripheral blood), mice were treated with either VEN (Venetoclax) or vehicle for 10 days followed by assessment of leukemia-free survival until disease manifestation for each recipient. These results obtained from larger groups of biological replicates precisely reflected the drug responses seen in the preclinical trial and, importantly, clearly corresponded to the degree of BCL-2 dependence assessed by mitochondrial priming: (i) PDX13 showed a minor delay of disease manifestation and low BCL-2 dependence (Fig. (Fig.3f,3f, mean survival difference 2.3 days, BAD-HRK priming 18.6%), (ii) in PDX10 we observed a significantly delayed onset of overt leukemia upon VEN therapy in line with clear BCL-2 dependence (Fig. (Fig.3g,3g, mean survival difference 43.2 days, BAD-HRK priming 56.8%), and (iii) PDX2 showed a prolonged survival with no leukemia manifestation in the VEN group within the observation period (Fig. (Fig.3h,3h, more than 70 days superior survival, BAD-HRK priming 80.3%) corresponding to a strong BCL-2 dependence.[3] |
| Enzyme Assay |
Binding affinities (Ki or IC50) of ABT-199 against different isoforms of Bcl-2 family are determined with competitive fluorescence polarization assays. The peptide probe and protein pairs used are as follows: : f-bad (1 nM) and Bcl-xL (6 nM), f-Bax (1 nM) and Bcl-2 (10 nM), f-Bax (1 nM) and Bcl-w (40 nM), f-Noxa (2 nM) and Mcl-1 (40 nM), and f-Bax (1 nM) and Bcl-2-A1 (15 nM). A time-resolved fluorescence resonance energy transfer assay is also used to determine the binding affinities for Bcl-xL. At room temperature, for 30 minutes, Bcl-xL (1 nM, His tagged), 200 nM f-Bak, 1 nM Tb-labeled anti-His antibody, and ABT-199 are combined.
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| Cell Assay |
RS4;11 cells are treated with ABT-199 (Venetoclax) diluted in half-log steps starting at 1 μM-0.05 nM after being seeded at a density of 5 × 104 per well in 96-well plates. ABT-199 (Venetoclax) is incubated with leukemia and lymphoma cell lines for 48 hours after they have been seeded at 1.5-2 × 104 cells per well in the appropriate medium. Using the Cell TiterGlo reagent, effects on proliferation are assessed. The concentration-response data are analyzed using nonlinear regression to determine the EC50 values.[1]
Cells from T-ALL cell lines (supplemental Table 1, available on the Blood Web site) were plated at 100 000 cells per well in 96-well plates. The cells were incubated for 48 hours in 100 µL medium with 10% FBS to which 5 µL of the appropriate ABT-199 (Venetoclax) dilution or dimethylsulfoxide (DMSO) was added. [2] Cell viability assays were performed upon culturing of cells in RPMI 1640 supplemented with 20% FCS and 1% l-glutamine. Cells were exposed to 11 different concentrations of VEN (Venetoclax) (0.1 nM, 1 nM, 10 nM, 50 nM, 100 nM, 250 nM, 500 nM, 1 µM, 3 µM, 5 µM, and 10 µM) for 72 h (BCP-ALL cell lines) or 24 h (BCP-ALL PDX cells). [3] |
| Animal Protocol |
Mice: Nonobese diabetic/severe combined immunodeficient γ (NSG) mice are given a 150 µL injection of phosphate-buffered saline containing 5×106 luciferase-labeled LOUCY cells at the age of 6 weeks in the tail vein.
The IVIS Lumina II imaging system measures the bioluminescence at regular intervals. After the cells have engrafted and the mice have been randomly split into two groups at 6 weeks (each group contains an equal number of males and females), the treatment is initiated on day 0 of the experiment. Venetoclax (ABT-199) 100 mg/kg body weight or vehicle is administered orally to mice for 4 days in a row. Days 0, 2, and 4 are used to measure the bioluminescene.[1]
Nonobese diabetic/severe combined immunodeficient γ (NSG) mice were injected at 6 weeks of age in the tail vein with 150 µL phosphate-buffered saline containing 5 × 106 luciferase-labeled LOUCY cells. At regular time points, the bioluminescence was measured using the IVIS Lumina II imaging system. At 6 weeks, the cells were engrafted and the mice were randomly divided into 2 groups (with an equal number of males and females in both groups), and the treatment was started on day 0. Mice were treated with 100 mg ABT-199/kg body weight or with vehicle via oral gavage for 4 consecutive days. Venetoclax (ABT-199) was formulated in 60% phosal 50 propylene glycol, 30% polyethylene glycol 400, and 10% ethanol. At days 0, 2, and 4 the bioluminescene was measured. Before imaging, the mice were injected intraperitoneally with 200 µL of a 15 mg/mL firefly d-luciferin potassium salt solution and anesthetized by inhalation of 5% isoflurane. The mice were imaged 10 minutes after luciferin injection. The total bioluminescence signal in each mouse was calculated via the region of interest tool (total counts) in the Living Image software.[2] A xenograft of primary human T-ALL cells from patient 3 was established in NSG mice by retro-orbital injection. Upon establishment of disease, human leukemic cells were isolated from the spleen and retransplanted into secondary recipients. Next, tertiary xenograft injections were performed in a cohort of 10 NSG mice and leukemia engraftment was monitored by human CD45 staining in peripheral blood using FACS analysis with the S3 cell sorter. Upon detection of human CD45+ leukemic blasts in peripheral blood, mice were randomized in 2 groups and treated with vehicle or 100 mg Venetoclax (ABT-199)/kg body weight for 7 consecutive days. After treatment, animals were sacrificed and the percentage human CD45-positive leukemic blasts in bone marrow were determined by FACS as described above.[2] Upon transplantation of ALL cells, engraftment of human blasts was monitored in peripheral blood by flow cytometry surface staining for huCD19 and huCD4549,50. Mice were treated with vehicle (60% Phosal 50 PG, 30% polyethylene glycol and 10% ethanol) or VEN (Venetoclax) 100 mg/kg/day orally for 10 days. Treatment was initiated on day 21 post transplantation (Fig. (Fig.3a)3a) or upon engraftment of more than 5% blasts in the peripheral blood (Fig. 3f–h). Posttreatment survival times were defined as manifestation of clinically overt leukemia in recipient animals upon initiation of treatment. Manifestation of leukemia was confirmed by flow cytometry staining of bone marrow and spleen cells as described above showing high percentages of human ALL in the respective compartments. For the independent cohort (Fig. (Fig.4)4) treatment was carried out as previously described.[3] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Following multiple oral doses after a meal, peak plasma concentrations of venetoclax are reached 5–8 hours post-dose. The steady-state AUC (area under the curve) of venetoclax increases proportionally with the dose range of 150–800 mg. At a once-daily dose of 400 mg after a low-fat meal, the mean (± standard deviation) steady-state Cmax of venetoclax is 2.1 ± 1.1 μg/mL, and the AUC0–24 is 32.8 ± 16.9 μg•h/mL. Compared to a fasting state, venetoclax exposure increases 3.4-fold after a low-fat meal and 5.2-fold after a high-fat meal. Both Cmax and AUC increase by 50% after a high-fat meal compared to a low-fat meal. The FDA label indicates that venetoclax should be taken with food. Following a single oral dose of 200 mg of radiolabeled [14C]-venetoclax in healthy subjects, the dose detected in feces exceeded 99.9% within 9 days, while the dose detected in urine was less than 0.1%, indicating that hepatic clearance is the primary route of venetoclax clearance from systemic circulation. Unmetabolized venetoclax accounted for 20.8% of the fecal excretion of radioactive dose. The population estimate for the apparent volume of distribution (Vdss/F) of venetoclax ranges from 256 to 321 liters. Primarily metabolized by the liver. Metabolism/MetabolitesIn vitro studies have shown that venetoclax is primarily metabolized as a substrate for CYP3A4/5. Biological half-lifeThe half-life of venetoclax has been reported to be 19–26 hours after a single dose of 50 mg. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In a clinical trial of 240 patients with chronic lymphocytic leukemia (CLL), 20% of subjects treated with venecraleum experienced elevated serum transaminases; however, these elevations were usually transient, mild, and without jaundice or other symptoms. No clinically significant liver injury associated with venecraleum was reported in pre-registration trials, and only a small number of patients required discontinuation due to abnormal liver function. Since its approval, clinical use of venecraleum has been limited, but no cases of clinically significant liver injury have been identified. Venecraleum reduces the total white blood cell count and may cause lymphopenia in addition to neutropenia. Therefore, venecraleum may induce immune responses, including reactivation of hepatitis B virus (HBV). However, there are currently no reported cases of HBV reactivation, and detailed information on the effects of venecraleum on HBV levels in patients with a history of hepatitis B or evidence of prior infection is lacking. Probability Score: E (Unlikely to cause clinically significant liver injury). Use during pregnancy and lactation ◉ Overview of use during lactation There is currently no information regarding the use of venetoclax during lactation. Because venetoclax binds to plasma proteins at a rate exceeding 99%, its concentration in breast milk is likely to be low. However, its half-life of 26 hours may allow it to accumulate in the infant. Most sources consider breastfeeding contraindicated during maternal treatment with anti-tumor drugs. The manufacturer recommends discontinuing breastfeeding during venetoclax treatment and for one week after the last dose. Chemotherapy may adversely affect the normal microbiota and chemical composition of breast milk. Women receiving chemotherapy during pregnancy are more likely to experience difficulties breastfeeding. ◉ Effects on breastfed infants No published information found as of the revision date. ◉ Effects on lactation and breast milk No published information found as of the revision date. Protein Binding Venetoc is highly bound to human plasma proteins, with a free fraction in plasma <0.01 within a concentration range of 1-30 µM (0.87-26 µg/mL). The mean plasma-to-serum ratio is 0.57. |
| References |
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| Additional Infomation |
Venetoclax is a first-in-class, orally bioavailable selective small-molecule inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (BCL-2), belonging to the pyrrolopyridine class. It functions by mimicking BH3-only proteins and binding directly to the hydrophobic groove of BCL-2, thereby displacing pro-apoptotic proteins such as BIM. This action leads to mitochondrial outer membrane permeabilization, activation of caspase enzymes, and restoration of apoptosis in cancer cells that overexpress BCL-2. Unlike navitoclax, which inhibits both BCL-2 and BCL-X(L), venetoclax selectively targets BCL-2 without affecting BCL-X(L), thus avoiding BCL-X(L)-mediated thrombocytopenia. Venetoclax also acts as a P-glycoprotein inhibitor. It was initially approved by the FDA in April 2016 for chronic lymphocytic leukemia (CLL) with 17p deletion. In 2018, its indication was expanded to include patients with CLL or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy. Venetoclax is approximately 10 times more potent than navitoclax at inducing apoptosis in CLL cells. While associated with a low rate of transient serum enzyme elevations and no reported cases of clinically apparent acute liver injury with jaundice, venetoclax has potent immunosuppressive activity and may cause reactivation of hepatitis B.
Pharmacodynamics Venetoclax rapidly and effectively induces apoptosis in chronic lymphocytic leukemia (CLL) cells, with its action occurring within 24 hours and leading to tumor lysis syndrome. Venetoclax selectively targets BCL2, has a good safety profile, and has been shown to significantly improve the condition of patients with relapsed CLL or SLL, including those with poor prognosis. The drug is not expected to have a significant effect on the cardiac QT interval. Venetoclax has been shown to be effective against various lymphatic system malignancies, including relapsed/refractory CLL with 17p deletion, with an overall response rate of approximately 80%. |
| Molecular Formula |
C45H50CLN7O7S
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| Molecular Weight |
868.44
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| Exact Mass |
867.318
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| Elemental Analysis |
C, 62.24; H, 5.80; Cl, 4.08; N, 11.29; O, 12.90; S, 3.69
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| CAS # |
1257044-40-8
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| Related CAS # |
Venetoclax-d8;1257051-06-1
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| PubChem CID |
49846579
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| Appearance |
Yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.644
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| LogP |
10.88
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
61
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| Complexity |
1640
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(NS(=O)(C1=CC=C(NCC2CCOCC2)C([N+]([O-])=O)=C1)=O)C3=CC=C(N4CCN(CC5=C(C6=CC=C(Cl)C=C6)CC(C)(C)CC5)CC4)C=C3OC7=CN=C(NC=C8)C8=C7
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| InChi Key |
LQBVNQSMGBZMKD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C45H50ClN7O7S/c1-45(2)15-11-33(39(26-45)31-3-5-34(46)6-4-31)29-51-17-19-52(20-18-51)35-7-9-38(42(24-35)60-36-23-32-12-16-47-43(32)49-28-36)44(54)50-61(57,58)37-8-10-40(41(25-37)53(55)56)48-27-30-13-21-59-22-14-30/h3-10,12,16,23-25,28,30,48H,11,13-15,17-22,26-27,29H2,1-2H3,(H,47,49)(H,50,54)
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| Chemical Name |
4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
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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) |
DMSO: ~100 mg/mL (~115.1 mM)
Water: <1 mg/mL(slightly soluble or insoluble) Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 5 mg/mL (5.76 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (2.88 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: 2.5 mg/mL (2.88 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 heating and sonication. Solubility in Formulation 4: 5% DMSO+50% PEG 300+5% Tween 80+ddH2O: 5 mg/mL Solubility in Formulation 5: 20 mg/mL (23.03 mM) in 60% phosal 50 propylene glycol (PG), 30% polyethylene glycol 400 (PEG400), 10% ethanol (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1515 mL | 5.7575 mL | 11.5149 mL | |
| 5 mM | 0.2303 mL | 1.1515 mL | 2.3030 mL | |
| 10 mM | 0.1151 mL | 0.5757 mL | 1.1515 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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