ABX464
(Synonyms: ABX464) 目录号 : GC32145
ABX464 (SPL-464) is a novel anti-HIV molecule that inhibits HIV-1 replication in stimulated peripheral blood mononuclear cells (PBMCs) from 5 different donors with IC50 ranging between 0.1 μM and 0.5 μM.
Cas No.:1258453-75-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | The concentration of ABX464 with minimal side effects on cell viability is determined using an MTS test. PBMCs are treated with ABX464 (2, 4, 8, 16, 31, 63, 125, and 250 μM). Cell viability is measured by MTS assay after 6 days of incubation and cytotoxicity is indicated as percentage as compared with untreated cells[1]. |
Animal experiment: | Mice[1]SCID mice are reconstituted with fresh human PBMCs for two weeks and the reconstitution rates are estimated by human IgG titration. Reconstituted SCID mice are infected with JRCSF HIV-1 strain by intraperitoneal injection. Control group receive labrafil and 5% DMSO by gavage (n=15) and the treated group receive 20 mg/kg b.i.d of ABX464 (n=14) for 15 days[1]. |
References: [1]. Campos N, et al. Long lasting control of viral rebound with a new drug ABX464 targeting Rev-mediated viral RNA biogenesis. Retrovirology. 2015 Apr 9;12:30. | |
ABX464 (SPL-464) is a novel anti-HIV molecule that inhibits HIV-1 replication in stimulated peripheral blood mononuclear cells (PBMCs) from 5 different donors with IC50 ranging between 0.1 μM and 0.5 μM.
[1] No?lie Campos, et al. Retrovirology. 2015 Apr 9;12:30.
| Cas No. | 1258453-75-6 | SDF | |
| 别名 | ABX464 | ||
| Canonical SMILES | FC(F)(F)OC1=CC=C(NC2=NC3=C(Cl)C=CC=C3C=C2)C=C1 | ||
| 分子式 | C16H10ClF3N2O | 分子量 | 338.71 |
| 溶解度 | DMSO : ≥ 100 mg/mL (295.24 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.9524 mL | 14.7619 mL | 29.5238 mL |
| 5 mM | 0.5905 mL | 2.9524 mL | 5.9048 mL |
| 10 mM | 0.2952 mL | 1.4762 mL | 2.9524 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
ABX464 (obefazimod) for moderate-to-severe, active ulcerative colitis: a phase 2b, double-blind, randomised, placebo-controlled induction trial and 48 week, open-label extension
Lancet Gastroenterol Hepatol 2022 Nov;7(11):1024-1035.PMID:36075249DOI:10.1016/S2468-1253(22)00233-3.
Background: ABX464 (obefazimod) is a small molecule that selectively upregulates miR-124 in immune cells. We aimed to assess ABX464 as a treatment for patients with moderate-to-severe, active ulcerative colitis. Methods: In this phase 2b, double-blind, randomised, placebo-controlled induction trial, patients were recruited from 95 centres (hospitals and health-care centres) in 16 countries. Eligible patients were aged 18-75 years, with a diagnosis of moderate-to-severe, active ulcerative colitis and a modified Mayo Score (MMS) of 5 points or higher, and a documented non-response or intolerance to previous treatment. Enrolled patients were randomly assigned (1:1:1:1) via an interactive voice and web response system to receive once daily oral ABX464 100 mg, ABX464 50 mg, ABX464 25 mg, or matched placebo. Randomisation was stratified according to study site (US vs non-US) and to whether the patient had previous exposure to second-line treatment with biologics or JAK inhibitors. The primary endpoint was the change from baseline in MMS at week 8. The primary efficacy analysis was done in the full analysis set (FAS), defined as all randomly assigned patients who received at least one dose of study treatment and had baseline data for at least one efficacy variable, and was analysed according to the principles of intention-to-treat. Safety analyses included patients who had been randomly assigned and who received at least one dose of study treatment. The 96 week open-label extension is ongoing. This study is registered with ClinicalTrials.gov, NCT04023396. Findings: Between Aug 13, 2019, and April 16, 2021, 254 patients were randomly allocated to ABX464 100 mg (n=64), ABX464 50 mg (n=63), ABX464 25 mg (n=63), or placebo (n=64). Two patients, both in the ABX464 25 mg group, were excluded from the FAS. In the FAS at week 8, the least squares mean (LSM) change from baseline in MMS was -2·9 (95% CI -3·4 to -2·5) for the ABX464 100 mg group, -3·2 (-3·7 to -2·7) for the ABX464 50 mg group, -3·1 (-3·6 to -2·6) for the ABX464 25 mg group, and -1·9 (-2·4 to -1·5) for placebo group; the magnitude of the difference in MMS from baseline was significantly greater in all three ABX464 groups compared with placebo (p=0·0039 for ABX464 100 mg vs placebo, p=0·0003 for ABX464 50 mg vs placebo, and p=0·0010 for ABX464 25 mg vs placebo). The most frequently reported adverse event was headache, which was reported for 27 (42%) of 64 patients in the ABX464 100 mg group, 19 (30%) of 63 in the 50 mg group, 13 (21%) of 62 in the 25 mg group, and five (8%) of 64 in the placebo group. Severe (grade 3) headache was reported for three (5%) patients in the ABX464 group 100 mg group, two (3%) in the ABX464 50 mg group, one (2%) in the ABX464 25 mg group, and none in the placebo group. The only serious adverse event reported for two or more patients in any group was ulcerative colitis (one in each of the ABX464 100 mg and 50 mg groups, and three [5%] in the placebo group). Interpretation: All doses of ABX464 significantly improved moderate-to-severe, active ulcerative colitis compared with placebo, as measured by changes in MMS from baseline to week 8. A phase 3 clinical programme is ongoing. Funding: Abivax.
ABX464 (obefazimod) up-regulates miR-124 to reduce pro-inflammatory markers in inflammatory bowel diseases
Clin Transl Gastroenterol 2022 Dec 26.PMID:36573890DOI:10.14309/ctg.0000000000000560.
Advanced therapies have transformed the treatment of inflammatory bowel disease; however, many patients fail to respond, highlighting the need for therapies tailored to the underlying cell and molecular disease drivers. The first-in-class oral molecule ABX464 (obefazimod), which selectively up-regulates miR-124, has demonstrated its ability to be a well-tolerated treatment with rapid and sustained efficacy in patients with ulcerative colitis (UC). Here, we provide evidence that ABX464 impacts the immune system in vitro, in murine model of IBD, as well as in patients with UC. In vitro, ABX464 treatment up-regulated miR-124 and led to decreases in proinflammatory cytokines including IL17 and IL6, and in the chemokine CCL2. Consistently, miR-124 expression was upregulated in the rectal biopsies and blood samples of UC patients and a parallel reduction in Th17 cells and IL17a levels was observed in serum samples. In a mouse model of induced intestinal inflammation with dextran sulfate sodium, ABX464 reversed the increases in multiple proinflammatory cytokines in the colon and the upregulation of IL17a secretion in the mesenteric lymph nodes. By up-regulating miR-124, ABX464 acts as "a physiological brake" of inflammation which may explain the efficacy of ABX464 with a favorable tolerability and safety profile in UC patients.
ABX464 Decreases the Total Human Immunodeficiency Virus (HIV) Reservoir and HIV Transcription Initiation in CD4+ T Cells From Antiretroviral Therapy-Suppressed Individuals Living With HIV
Clin Infect Dis 2022 Jun 10;74(11):2044-2049.PMID:34436569DOI:10.1093/cid/ciab733.
Background: Antiretroviral therapy (ART) intensification and disruption of latency have been suggested as strategies to eradicate HIV. ABX464 is a novel antiviral that inhibits HIV RNA biogenesis. We investigated its effect on HIV transcription and total and intact HIV DNA in CD4+ T cells from ART-suppressed participants enrolled in the ABIVAX-005 clinical trial (NCT02990325). Methods: Peripheral CD4+ T cells were available for analysis from 9 ART-suppressed participants who were treated daily with 150 mg of ABX464 for 4 weeks. Total and intact HIV DNA and initiated, 5'elongated, unspliced, polyadenylated, and multiply-spliced HIV transcripts were quantified at weeks 0, 4, and 8 using ddPCR. Results: We observed a significant decrease in total HIV DNA (P = .008, median fold change (mfc) = 0.8) and a lower median level of intact HIV DNA (P = not significant [n.s.], mfc = 0.8) after ABX464 treatment. Moreover, we observed a decrease in initiated HIV RNA per million CD4+ T cells and per provirus (P = .05, mfc = 0.7; P = .004, mfc = 0.5, respectively), a trend toward a decrease in the 5'elongated HIV RNA per provirus (P = .07, mfc = 0.5), and a lower median level of unspliced HIV RNA (P = n.s., mfc = 0.6), but no decrease in polyadenylated or multiply-spliced HIV RNA. Conclusions: In this substudy, ABX464 had a dual effect of decreasing total HIV DNA (and possibly intact proviruses) and HIV transcription per provirus. To further characterize its specific mechanism of action, long-term administration of ABX464 should be studied in a larger cohort. Clinical trials registration: NCT02990325.
Specific and selective induction of miR-124 in immune cells by the quinoline ABX464: a transformative therapy for inflammatory diseases
Drug Discov Today 2021 Apr;26(4):1030-1039.PMID:33387693DOI:10.1016/j.drudis.2020.12.019.
Inflammatory diseases are believed to develop as a result of dysregulated inflammatory responses to environmental factors on susceptible genetic backgrounds. Operating at the level of post-transcriptional gene regulation, miRNAs are a class of endogenous, small noncoding RNAs that can promote downregulation of protein expression by translational repression and/or mRNA degradation of target mRNAs involved in inflammation. MiR-124 is a crucial modulator of inflammation and innate immunity that could provide therapeutic restitution of physiological pathways lost in inflammatory diseases. A recently discovered small quinoline, ABX464, was shown to upregulate miR-124 in human immune cells. In vivo, in a proof-of-concept clinical study, ABX464 showed robust and consistent efficacy in ulcerative colitis (UC). In this review, we examine the current therapeutic options proposed for UC and discuss the drug candidate ABX464 in this context.
ABX464: a good drug candidate instead of a magic bullet
Retrovirology 2015 Jul 28;12:64.PMID:26215448DOI:10.1186/s12977-015-0189-x.
Despite the significant number of antiviral drugs that are currently available in the clinics of developed countries, none of these affect the production stage of HIV-1 replication, more specifically the process of viral gene expression. For instance, several early attempts failed to generate inhibitors of the viral Tat protein, the small activator of viral transcription from the long terminal repeat (LTR) promoter. A recent study published in Retrovirology by Campos et al. presents a new small molecule inhibitor, ABX464, that targets the other small viral protein essential for viral gene expression, the Rev protein (Retrovirology 12:30, 2015). Targeting of multiple virus replication steps and silencing the generation of new progeny may be of particular value for current attempts to develop novel therapeutic strategies that provide a cure or functional cure for HIV-1 infection (Nat Rev Immunol 12: 607-614, 2012). We will briefly review some of the unique antiviral properties of ABX464, with the focus on its surprising ability to exhibit a sustained antiviral effect in a humanized mouse model. Although ABX464 may remain an important new addition to the anti-HIV arsenal, we do present a sobering alternative explanation for the long-lasting reduction in viral load after treatment cessation.