| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
Purity: ≥98%
Alobresib (GS-5829) is a novel and potent BET bromodomain inhibitor with anticancer activity. IIt may be used to treat USCs that are recurrent or chemotherapy-resistant and overexpress c-Myc.
| Targets |
BET; BLK; Akt; ERK1/2; MYC
Alobresib targets BET bromodomain proteins including BRD2, BRD3, BRD4, and BRDT.[1] |
|---|---|
| ln Vitro |
In-vitro research shows that USC cell lines are highly sensitive to the drug GS-5829, which results in a dose-dependent reduction in the level of phosphorylated c-Myc and an increase in caspase activation (apoptosis).[1] Through the deregulation of important signaling pathways like BLK, AKT, ERK1/2, and MYC, GS-5829 reduces CLL cell proliferation and triggers leukemia cell apoptosis. According to IκBα modulation, GS-5829 also suppresses NF-κB signaling. An imbalance between the positive (BIM) and negative (BCL-XL) regulators of the intrinsic apoptosis pathway causes GS-5829-induced apoptosis.[2]
Alobresib inhibited cell proliferation in primary USC cell lines in a dose-dependent manner, as demonstrated in ARK1 and ARK2 cells following 72-hour incubation with increasing concentrations (0.001 μM to 5 μM). No significant differences in IC50 values were noted between Alobresib, GS-626510, and JQ1 in ARK1, ARK2, or six additional USC cell lines. Alobresib treatment caused a dose-dependent decrease in phosphorylated c-Myc levels and a dose-dependent increase in caspase activation (apoptosis) in USC cell lines.[1] |
| ln Vivo |
GS-5829 has impressive activity against USC primary tumors as well as USC xenografts. In tumors exposed to GS-5829, analysis of the expression of c-Myc shows that both the total and phosphorylated forms of the protein are downregulated. When compared to JQ1 at the doses used in in vivo experiments against USC xenografts, GS-5829 significantly outperforms it in terms of bioavailability after oral administration. There is a need for clinical studies with the drug GS-5829 in USC patients who have disease that is resistant to conventional salvage chemotherapy. [1]
In USC-ARK2 xenograft models, twice daily oral administration of Alobresib at 10 mg/kg and 20 mg/kg for 28 days significantly slowed tumor growth compared to vehicle control and to daily intraperitoneal JQ1 (50 mg/kg/day) (p < 0.05 starting on dosing day 21). Tumor tissue weights recorded on day 28 confirmed a statistically significant difference between control and treated groups. In PK/PD studies, a single oral dose of Alobresib at 10, 20, or 40 mg/kg in USC-ARK2 tumor-bearing animals resulted in significant in vivo modulation of c-Myc expression compared to vehicle (p < 0.05). Immunohistochemistry on tumor tissues after 28 days of twice daily Alobresib (10 or 20 mg/kg) also showed significant c-Myc downregulation.[1] |
| Cell Assay |
Following the manufacturer's instructions, MEC-1 cells treated for 72 hours with GS-5829 or the BCR signaling inhibitors are subjected to the TACS XTT cell proliferation/viability assay (Trevigen). Using technical triplicate measurements, half-maximal inhibitory concentrations (IC50) are computed.
For cell viability assays, cells were seeded at 40,000 cells per well in 6-well microtiter plates. After 24 hours, cells were treated with scalar amounts of Alobresib ranging from 0.001 μM to 5 μM. Three days after treatment, cells were harvested, stained with propidium iodide, and counted by flow cytometry. The number of viable cells in each well was normalized to control wells, and IC50 values were determined by comparing log10 drug concentration to percentage of viable cells using a non-parametric 3-parameter regression using Prism 6 software. All experiments were completed in at least triplicate. For apoptosis assessment, IncuCyte Caspase 3/7 activity assay was performed (though primarily described for GS-626510, the study states that Alobresib also caused a dose-dependent increase in caspase activation). Cells were cultured in 96-well plates at 3,000 cells/well, treated with 3-fold serial dilutions of compound, and kinetic activation of Caspase 3/7 was monitored using a fluorescence imaging system every 3 hours for 72 hours.[1] |
| Animal Protocol |
female CB17/lcrHsd-Prkd/scid mice bearing USC-ARK1 or USC-ARK2 xenograft
20 mg/kg, 10 mg/kg Oral gavage For in vivo efficacy studies, female CB17/lcrHsd-Prkdc/scid mice were injected subcutaneously with USC-ARK2 cells (7 × 10^6 cells in 0.3 mL PBS with 50% Matrigel) into the lower abdomen. When mean tumor burden reached 150–300 mg (target 200 mg), mice were triaged into treatment groups. Alobresib was administered via oral gavage twice daily for 28 days at doses of 10 mg/kg and 20 mg/kg. JQ1 was dosed intraperitoneally at 50 mg/kg/day. Tumor measurements and mouse weights were recorded at least twice weekly. Tumor volumes were calculated as 0.5 × (width² × height). On day 28, animals were euthanized, and blood and tumors were collected. For pharmacokinetic/pharmacodynamic studies, female CB17/lcrHsd-Prkdc/scid mice bearing USC-ARK2 tumors were treated with a single oral dose of Alobresib at 40, 20, or 10 mg/kg. Blood was collected via cardiac puncture under isoflurane anesthesia at 1 and 6 hours post-treatment (3 animals per time point) into K2EDTA tubes. Plasma was obtained by centrifugation (2000 × g, 5 minutes) and frozen at -80°C. Tumors were excised, halved; one half frozen for PD studies, the other fixed in formalin for 24 hours then transferred to 70% ethanol for paraffin embedding and histopathological evaluation.[1] |
| ADME/Pharmacokinetics |
Alobresib demonstrated excellent oral bioavailability after a single administration in mice bearing USC-ARK2 tumors, as determined by LC/MS/MS analysis of plasma samples. Pharmacokinetic analysis of collected plasma showed excellent oral bioavailability .[1]
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| Toxicity/Toxicokinetics |
In vivo, twice daily oral doses of Alobresib at 10 mg/kg and 20 mg/kg were well tolerated in mice, with no clear impact on body weight compared to vehicle control. No evidence of acute or chronic toxicity was detected in treated animals, as demonstrated by lack of significant variation in behavior or body weights relative to control groups.[1]
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| References | |
| Additional Infomation |
Alobresib is being investigated in the clinical trial NCT02607228 (GS-5829: Safety, tolerability, pharmacokinetics, and pharmacodynamics of Alobresib as monotherapy and in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer). Alobresib is an orally bioavailable inhibitor of the bromodomain and terminal extradomain (BET) protein family with potential antitumor activity. After oral administration, Alobresib binds to the acetylated lysine recognition motif in the bromodomain of the BET protein, thereby preventing the interaction between the BET protein and acetylated histones. This disrupts chromatin remodeling and gene expression. Inhibition of certain growth-promoting genes may lead to the inhibition of the proliferation of BET-overexpressing tumor cells. The BET protein, composed of BRD2, BRD3, BRD4, and BRDT, is a transcriptional regulator that plays an important role in development and cell growth.
Alobresib (GS-5829) is a clinical compound being evaluated in multiple phase 1-2 clinical trials for solid tumors and lymphomas, including metastatic castrate-resistant prostate cancer and advanced estrogen receptor-positive HER2-negative breast cancer (ClinicalTrials.gov identifiers: NCT02392611, NCT02607228, NCT02983604). The study concludes that clinical studies with Alobresib in USC patients harboring chemotherapy-resistant disease are warranted. Alobresib was found more effective than JQ1 at the concentrations/doses used in comparative in vivo experiments against USC xenografts.[1] |
| Molecular Formula |
C26H23N5O2
|
|---|---|
| Molecular Weight |
437.4931
|
| Exact Mass |
437.185
|
| Elemental Analysis |
C, 71.38; H, 5.30; N, 16.01; O, 7.31
|
| CAS # |
1637771-14-2
|
| Related CAS # |
1637771-14-2
|
| PubChem CID |
86281210
|
| Appearance |
Off-white to light yellow solid powder
|
| LogP |
3.2
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
33
|
| Complexity |
672
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
CMSUJGUHYXQSOK-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C26H23N5O2/c1-15-23(16(2)33-31-15)18-13-19(24-20(14-18)29-25(30-24)17-9-10-17)26(32,21-7-3-5-11-27-21)22-8-4-6-12-28-22/h3-8,11-14,17,32H,9-10H2,1-2H3,(H,29,30)
|
| Chemical Name |
[2-cyclopropyl-6-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-benzimidazol-4-yl]-dipyridin-2-ylmethanol
|
| Synonyms |
Alobresib; GS 5829; GS5829; GS-5829
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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: 83.3~87 mg/mL (~198.9 mM)
Water: ˂1 mg/mL Ethanol: ~11 mg/mL (~25.1 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.75 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 20.8 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: ≥ 2.08 mg/mL (4.75 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 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.75 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2858 mL | 11.4288 mL | 22.8577 mL | |
| 5 mM | 0.4572 mL | 2.2858 mL | 4.5715 mL | |
| 10 mM | 0.2286 mL | 1.1429 mL | 2.2858 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02607228 | Terminated | Drug: Alobresib Drug: Enzalutamide |
Metastatic Castrate-Resistant Prostate Cancer |
Gilead Sciences | December 8, 2015 | Phase 1 Phase 2 |
| NCT02392611 | Completed | Drug: Alobresib Drug: Exemestane |
Solid Tumors and Lymphomas | Gilead Sciences | March 16, 2015 | Phase 1 |
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