Tapinarof (WBI 1001)
(Synonyms: 苯烯莫德; WBI-1001; Benvitimod; GSK2894512) 目录号 : GC31732
Tapinarof (GSK2894512, Benvitimod, WBI 1001, DHPS, DMVT 505) is a natural agonist of aryl hydrocarbon receptor (AhR) and induces nuclear translocation of AhR in immortalized keratinocytes (HaCaT) with EC50 of 0.16 nM. Tapinarof induces cellular apoptosis in CD4+ T cells in a dosedependent manner with IC50 of 5.2 μM.
Cas No.:79338-84-4
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: | HaCaT cells (10,000 cells/well) are cultured in 96-well Greiner μCLEAR plates in 100 μL DMEM with HEPES, Glutamax and 10% fetal bovine serum to confluence. Media is replaced with 100 μL media containing 0.2% heat-inactivated, charcoal-stripped fetal bovine serum and incubated overnight. Titrating concentrations of Tapinarof (10-8 μM ,10-6 μM, 10-4 μM, 0.01 μM, and 1 μM) are added for 30 minutes followed by washing and fixing in ice-cold methanol:acetone (50:50). Samples are blocked with 3% BSA for 1 hour, and then washed again in phosphate buffered saline with 0.1% Tween-20. Next, cells are stained with 50 μL of 1:50 dilution anti-AhR antibody in 3% BSA, followed by 50 μL secondary antibody (1:500 dilution chicken anti-rabbit AlexaFluor488 and 1:2,000 dilution Hoechst 33342) in 3% BSA/phosphate buffered saline. Images are acquired on InCell 2000 and/or Opera. Image analysis is performed using InCell Analyzer Workstation and/or Columbus[1]. |
Animal experiment: | Mice[1]Female BALB/c mice (BALB/cByJRj) are used. Studies are performed using 100 µL of Tapinarof (1%) or FICZ (0.01%, at the limit of solubility) in 60% ethanol: 40% water[1]. |
References: [1]. Smith SH, et al. Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans. J Invest Dermatol. 2017 Oct;137(10):2110-2119. | |
Tapinarof (GSK2894512, Benvitimod, WBI 1001, DHPS, DMVT 505) is a natural agonist of aryl hydrocarbon receptor (AhR) and induces nuclear translocation of AhR in immortalized keratinocytes (HaCaT) with EC50 of 0.16 nM. Tapinarof induces cellular apoptosis in CD4+ T cells in a dosedependent manner with IC50 of 5.2 μM.
Tapinarof binds and activates AhR in multiple cell types, including cells of the target tissue –human skin. In addition, tapinarof moderates proinflammatory cytokine expression in stimulated peripheral blood CD4+ T cells and ex vivo human skin, and impacts barrier gene expression in primary human keratinocytes; both of these processes are likely to be downstream of AhR activation based on current evidence.[1]
The anti-inflammatory properties of tapinarof derive from AhR agonism is conclusively demonstrated using the mouse model of imiquimod-induced psoriasiform skin lesions. Topical treatment of AhR-sufficient mice with tapinarof leads to compound-driven reductions in erythema, epidermal thickening and tissue cytokine levels. In contrast, tapinarof has no impact on imiquimod-induced skin inflammation in AhR-deficient mice.[1]
[1] Susan H Smith, et al. J Invest Dermatol. 2017 Oct;137(10):2110-2119.
| Cas No. | 79338-84-4 | SDF | |
| 别名 | 苯烯莫德; WBI-1001; Benvitimod; GSK2894512 | ||
| Canonical SMILES | OC1=C(C(C)C)C(O)=CC(/C=C/C2=CC=CC=C2)=C1 | ||
| 分子式 | C17H18O2 | 分子量 | 254.32 |
| 溶解度 | DMSO : ≥ 125 mg/mL (491.51 mM) | 储存条件 | 4°C, protect from light |
| 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 | 3.9321 mL | 19.6603 mL | 39.3205 mL |
| 5 mM | 0.7864 mL | 3.9321 mL | 7.8641 mL |
| 10 mM | 0.3932 mL | 1.966 mL | 3.9321 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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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，
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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。
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Phase 3 Trials of Tapinarof Cream for Plaque Psoriasis
Background: Tapinarof cream is a topical aryl hydrocarbon receptor-modulating agent under investigation for the treatment of psoriasis. Tapinarof modulates the expression of interleukin-17 and the skin-barrier proteins filaggrin and loricrin. Methods: We conducted two identical phase 3 randomized trials of tapinarof in patients with mild-to-severe plaque psoriasis. Adults with a baseline Physician's Global Assessment (PGA) score of 2 (mild) to 4 (severe) (on a scale from 0 to 4, with higher scores indicating more severe psoriasis) and a percent of total body-surface area affected of 3 to 20% were randomly assigned in a 2:1 ratio to use tapinarof 1% cream or vehicle cream once daily for 12 weeks. The primary end point, PGA response, was a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points at week 12. Secondary efficacy end points at week 12 were a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) score, a PGA score of 0 or 1, the mean change from baseline in the percent of body-surface area affected, and a reduction of at least 90% in the PASI score. Patient-reported outcomes were the mean changes from baseline to week 12 in the proportion of patients who had a decrease of at least 4 points in the Peak Pruritus Numeric Rating Scale (PP-NRS) score (range, 0 [no itch] to 10 [worst imaginable itch]), the PP-NRS total score, the Dermatology Life Quality Index total score, and the Psoriasis Symptom Diary score. Results: In trials 1 and 2, a total of 692 and 674 patients, respectively, were screened, with 510 and 515 patients being enrolled. A PGA response occurred in 35.4% of the patients in the tapinarof group and in 6.0% of those in the vehicle group in trial 1 and in 40.2% and 6.3%, respectively, in trial 2 (P<0.001 for both comparisons). Results for secondary end points and patient-reported outcomes were generally in the same direction as those for the primary end point. Adverse events with tapinarof cream included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus. Conclusions: Tapinarof 1% cream once daily was superior to vehicle control in reducing the severity of plaque psoriasis over a period of 12 weeks but was associated with local adverse events and headache. Larger and longer trials are needed to evaluate the efficacy and safety of tapinarof cream as compared with existing treatments for psoriasis. (Funded by Dermavant Sciences; PSOARING 1 and 2 ClinicalTrials.gov numbers, NCT03956355 and NCT03983980, respectively.).
New treatments in atopic dermatitis
Objective: To discuss the efficacy and safety of novel and emerging topical and systemic therapeutic agents for atopic dermatitis (AD).
Data sources: The review of the published literature was performed using the PubMed database, published abstracts and virtual presentations from scientific meetings, posted results on ClinicalTrials.gov, and data from industry press releases.
Study selections: Primary manuscripts with trial results, case reports, case series, clinical trial data from ClinicalTrials.gov, and articles highlighting expert perspectives on management of AD were selected.
Results: Emerging topical and systemic therapies primarily target the type 2 immune pathway. Moreover, 2 newer targeted medications are now approved by the Food and Drug Administration for both children and adults, crisaborole 2% ointment and dupilumab, with several others in the therapeutic pipeline. New directions in developing topical medications include Janus kinase inhibitors, tapinarof (an aryl hydrocarbon receptor agonist), and agents to correct microbial dysbiosis. In addition to the subcutaneously injected monoclonal antibody targeting the interleukin (IL) 4 receptor (dupilumab), other biologics targeting IL-13, IL-31, IL-33, OX40, and thymic stromal lymphopoietin are currently being tested. Oral Janus kinase inhibitors are showing outstanding efficacy and no serious safety signs, but safety concerns remain.
Conclusion: Given the tremendous burden of AD on physical, mental, and social health, the need is high to develop new, targeted therapies. Advances in our understanding of AD pathogenesis have paved the way toward the development of new therapies that promise to revolutionize our management of AD. Future research will focus on long-term efficacy and safety and creating predictive models for choosing best management options on a personalized basis.
Tapinarof in the treatment of psoriasis: A review of the unique mechanism of action of a novel therapeutic aryl hydrocarbon receptor-modulating agent
Tapinarof, a novel, first-in-class, small-molecule topical therapeutic aryl hydrocarbon receptor (AhR)-modulating agent, is in clinical development for the treatment of psoriasis and atopic dermatitis. The efficacy of tapinarof in psoriasis is attributed to its specific binding and activation of AhR, a ligand-dependent transcription factor, leading to the downregulation of proinflammatory cytokines, including interleukin 17, and regulation of skin barrier protein expression to promote skin barrier normalization. AhR signaling regulates gene expression in immune cells and skin cells and has critical roles in the regulation of skin homeostasis. Tapinarof-mediated AhR signaling underlies the mechanistic basis for the significant efficacy and acceptable tolerability observed in early-phase clinical trials of tapinarof cream in the treatment of psoriasis.
New Topical Therapies for Psoriasis
Psoriasis is a chronic immune-mediated skin disease with a significant impact on patients' quality of life. Mild-to-moderate forms of the disease usually require long-term topical treatment, but prolonged use of corticosteroids and vitamin D analogues is limited by adverse effects. With further understanding of psoriasis pathogenesis, new molecules are emerging aiming to fulfil these clinical needs. Tapinarof, an aryl hydrocarbon receptor modulator, has completed a phase III study and demonstrated good efficacy results, even in long treatment courses, with a favourable safety profile. It additionally appears to have a promising remitting effect as patients presented with an average relapsing time of over 3 months. Roflumilast, a phosphodiesterase type 4 inhibitor, also underwent a phase III study with significant lesion improvement and notable pruritus management, and with no reported side effects. Roflumilast was evaluated as an option for intertriginous areas with good outcomes in a small sample, but larger trials are required. The Janus kinase-signal transducer and activator of transcription pathway has been targeted in recent clinical investigations with promising options, currently with brepocitinib pending phase IIb results. Ongoing preclinical studies involving interleukin-2 inhibition, RNA modulators and amygdalin analogues may lead to forthcoming clinical trials. New topical drugs are successfully emerging and future research comparing them to classical options will dictate their clinical role in the treatment of psoriasis.
Aryl Hydrocarbon Receptor in Atopic Dermatitis and Psoriasis
The aryl hydrocarbon receptor (AHR)/AHR-nuclear translocator (ARNT) system is a sensitive sensor for small molecular, xenobiotic chemicals of exogenous and endogenous origin, including dioxins, phytochemicals, microbial bioproducts, and tryptophan photoproducts. AHR/ARNT are abundantly expressed in the skin. Once activated, the AHR/ARNT axis strengthens skin barrier functions and accelerates epidermal terminal differentiation by upregulating filaggrin expression. In addition, AHR activation induces oxidative stress. However, some AHR ligands simultaneously activate the nuclear factor-erythroid 2-related factor-2 (NRF2) transcription factor, which is a master switch of antioxidative enzymes that neutralizes oxidative stress. The immunoregulatory system governing T-helper 17/22 (Th17/22) and T regulatory cells (Treg) is also regulated by the AHR system. Notably, AHR agonists, such as tapinarof, are currently used as therapeutic agents in psoriasis and atopic dermatitis. In this review, we summarize recent topics on AHR related to atopic dermatitis and psoriasis.