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Purity: ≥98%
Sabizabulin (VERU-111; ABI-231) is a novel and orally bioavailable tubulin inhibitor that has the potential to treat cancer. It is being developed by Veru Pharm in Phase III clinical trial for the treatment of advanced prostate cancer. VERU-111 is also being evaluated for treating COVID-19 in another phase III study, as it targets microtubules that transport viruses. The idea is that the drug could disrupt the microtubule traffic that the novel coronavirus uses to cause infection. VERU-111 binds to a different site from taxanes on tubulin called the 'colchicine binding site.' VERU-111 has high oral bioavailability and does not interact with multiple drug resistance proteins so it cannot be pumped out of the cancer cell; minimal drug to drug interactions especially not metabolized by CYP3A4 and has high activity against many tumor types including prostate, breast and ovarian cancers. Furthermore, it has activity against cancers that have become resistant to taxanes, vinca alkaloids and doxorubicin. In preclinical studies, VERU-111 has less neurotoxicity and leucopenia compared to other tubulin targeting agents. On April 11, 2022, Veru Pharm announced that sabizabulin demonstrated in a Phase III clinical trial a clinically and statistically meaningful reduction in deaths (55%) in hospitalized patients with moderate to severe COVID-19.
| Targets |
Tubulin protein/microtubule
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| ln Vitro |
In a dose- and time-dependent manner, VERU-111 (2.5-80 nM; 24-48 hours) suppresses the development of Panc-1, AsPC-1, and HPAF-II cells (24 hours: IC50 of 25, 35, and 35 nM, respectively; 48 hours: IC50 of 11.8, 15.5, and 25 nM, respectively) [4]. VERU-111 (5-20 nM; 24 hours) arrests Panc-1 and AsPC-1 cells in the G2/M phase in a dose-dependent manner [4]. VERU-111 (5-20 nM; 24 hours) demonstrates dose-dependent suppression of pro-caspase 3 and 9 and activation of caspase-3 and 9, promotes the production of Bax and Bad, and inhibits the expression of Bcl-2 AsPC-1 and Bcl-xl protein in Panc-1 cells [4].
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| ln Vivo |
Comparing the vehicle-treated group with VERU-111 (50 μg/mouse; intratumoral; three times a week for three weeks) demonstrated a significant reduction in tumor growth. Mice given VERU-111 did not exhibit any overt toxicity, even though they kept gaining weight [4].
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| Enzyme Assay |
In Vitro Tubulin Polymerization Assay[5,6]
According to the method described by Wang et al.,porcine brain tubulins (>97% pure) were mixed with general tubulin buffer (80 mM PIPES, 2.0 mM MgCl2, 0.5 mM EGTA, and 1 mM GTP) to reach a final concentration of 3 mg/mL at 4 °C. The tubulin polymerization assay was incubated at 37 °C in a SYNERGY 4 Microplate Reader immediately after mixing tubulin protein solution and the test compounds in a 96-well plate and monitored every 30 s for 65 min at 340 nm. The experiment was performed in duplicates with paclitaxel as a positive control for tubulin polymerization, and colchicine and ABI-274 as positive controls for tubulin depolymerization. SPR for Affinity Assay[5,6] Binding affinity with tubulin was analyzed using SPR technology in a Reichert4SPR system equipped with a dextran SPR sensor chip (Reichert Polycarboxylate Hydrogel Chip P/N 13206067). Then, 50 μg/mL tubulin was immobilized to the sensor chip surface to attain 12 000 μRIU. One of the four flow cells on the chip was left free as a negative control. 4v or colchicine at different concentrations was injected over the sensor chip surface for association analysis, followed by dissociation analysis. The experiment data were obtained at 25 °C with a running buffer PBST (8 mM Na2HPO4, 136 mM NaCl, 2 mM KH2PO4, 2.6 mM KCl, and 0.05% (v/v) Tween 20, pH 7.4). The equilibrium dissociation constant (KD) was calculated by a steady-state fitting mode with TraceDrawer software. |
| Cell Assay |
Cell proliferation assay [4]
Cell Types: Panc-1, AsPC-1, HPAF-II Cell Tested Concentrations: 2.5, 5, 10, 20, 40, 80 nM Incubation Duration: 24, 48 hrs (hours) Experimental Results: Inhibited the growth of PanCa cells and dose- and time-dependent manner. After 24 hrs (hours) of treatment, the IC50 of VERU-111 in Panc-1, AsPC-1, and HPAF-II were 25, 35, and 35 nM, respectively, and after 48 hrs (hours) of treatment they were 11.8, 15.5, and 25 nM, respectively. Apoptosis analysis [4] Cell Types: Panc-1, AsPC-1 Cell Tested Concentrations: 5, 10, 20 nM Incubation Duration: 24 hrs (hours) Experimental Results: Panc-1 and AsPC-1 cells arrested at G2/ M period method. Western Blot Analysis[4] Cell Types: AsPC-1 and Panc-1 Cell Tested Concentrations: 5, 10, 20 nM Incubation Duration: 24 hrs (hours) Experimental Results: Dose-dependent inhibition of Caspase 3 and 9 precursors and Caspase-3 and 9 9 in both activated AsPC-1 and Panc-1 cells. Induces the expression of Bax and Bad and inhibits the expression of Bcl-2 and Bcl-xl proteins. |
| Animal Protocol |
Animal/Disease Models: Sixweeks old female athymic nude mice (carrying AsPC-1 cells)
Doses: 50 μg/animal Route of Administration: intratumoral injection; 3 times a week for 3 weeks Experimental Results: Effectively inhibited tumor growth. |
| References |
[1]. Wang Q, et al. Structure-Guided Design, Synthesis, and Biological Evaluation of (2-(1H-Indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl) Methanone (ABI-231) Analogues Targeting the Colchicine Binding Site in Tubulin. J Med Chem. 2019 Jul 12.
[2]. Qinghui Wang, et al. Discovery of ABI-231 analogs targeting the colchicine site in tubulin for advanced melanoma. Cancer Research 76(14 Supplement):4848-4848. [3]. Vivek Kashyap, et al. ABI-231: A novel small molecule suppresses tumor growth and metastatic phenotypes of cervical cancer cells via targeting Human papilloma virus (HPV) E6 and E7. Cancer Research 78(13 Supplement):679-679. [4]. Kashyap VK, et al. Therapeutic efficacy of a novel βIII/βIV-tubulin inhibitor (VERU-111) in pancreatic cancer. J Exp Clin Cancer Res. 2019 Jan 23;38(1):29. [5]. Structure-Activity Relationship Study of Novel 6-Aryl-2-benzoyl-pyridines as Tubulin Polymerization Inhibitors with Potent Antiproliferative Properties. J Med Chem. 2020 Jan 23;63(2):827-846. [6]. Discovery of novel 2-aryl-4-benzoyl-imidazole (ABI-III) analogues targeting tubulin polymerization as antiproliferative agents. Discovery of novel 2-aryl-4-benzoyl-imidazole (ABI-III) analogues targeting tubulin polymerization as antiproliferative agents. |
| Additional Infomation |
Sabizabulin is an orally bioavailable, small molecule tubulin inhibitor, with potential antineoplastic, antiviral and anti-inflammatory activities. Upon oral administration, sabizabulin binds to the colchicine-binding site of alpha- and beta-tubulin subunits of microtubules and crosslinks the microtubules, thereby inhibiting microtubule polymerization in tumor blood vessel endothelial cells and tumor cells. This blocks the formation of the mitotic spindle and leads to cell cycle arrest at the G2/M phase. As a result, this agent disrupts the tumor vasculature, tumor blood flow, deprives tumor cells of nutrients, and induces apoptosis. In addition, as microtubules plays an important role in intracellular transport, the inhibition of its polymerization may disrupt the transport of the androgen receptor (AR) into the cell nucleus, as well as virus trafficking around the cell. This may decrease viral replication and assembly. Inhibition of tubulin polymerization may also inhibit the release of pro-inflammatory cytokines and disrupt inflammatory cell activities. Sabizabulin is not a substrate of P-glycoprotein (Pgp), an efflux pump that when overexpressed, may confer resistance to taxane agents.
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| Molecular Formula |
C21H19N3O4
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| Molecular Weight |
377.393265008926
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| Exact Mass |
377.14
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| Elemental Analysis |
C, 66.83; H, 5.07; N, 11.13; O, 16.96
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| CAS # |
1332881-26-1
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| Related CAS # |
2635953-17-0 (HCl);1332881-26-1;
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| PubChem CID |
53379371
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
28
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| Complexity |
534
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C)C1C(=C(C=C(C=1)C(C1=CN=C(C2=CNC3C=CC=CC2=3)N1)=O)OC)OC
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| InChi Key |
WQGVHOVEXMOLOK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H19N3O4/c1-26-17-8-12(9-18(27-2)20(17)28-3)19(25)16-11-23-21(24-16)14-10-22-15-7-5-4-6-13(14)15/h4-11,22H,1-3H3,(H,23,24)
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| Chemical Name |
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
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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 mg/mL (5.30 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 20.0 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. Solubility in Formulation 2: 2 mg/mL (5.30 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 ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 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 | 2.6498 mL | 13.2489 mL | 26.4978 mL | |
| 5 mM | 0.5300 mL | 2.6498 mL | 5.2996 mL | |
| 10 mM | 0.2650 mL | 1.3249 mL | 2.6498 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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