Minor structural modifications-sometimes single atom changes-can have a dramatic impact on the properties of compounds. This is illustrated here on structures related to known mTOR inhibitor Sapanisertib. Subtle changes in the hinge binder lead to strikingly different overall profiles with changes in physical properties, metabolism, and kinase selectivity.

With possible implications in multiple autoimmune diseases, the retinoic acid receptor‐related orphan receptor RORγ has become a sought‐after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N‐(2,4‐dimethylphenyl)‐N‐isobutyl‐2‐oxo‐1‐[(tetrahydro‐2H‐pyran‐4‐yl)methyl]‐2,3‐dihydro‐1H‐benzo[d]imidazole‐5‐sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL‐23‐induced mouse skin inflammation model.

Background Actinic keratoses (AK) are proliferations of neoplastic keratinocytes in the epidermis resulting from cumulative exposure to ultraviolet radiation (UVR), which are liable to transform into squamous cell carcinoma (SCC). Organ Transplant Recipients (OTR) have an increased risk of developing SCC as a consequence of long-term immunosuppressive therapy. The aim of this study was to determine the molecular signature of AKs from OTR prior to treatment with methyl aminolevulinate-photodynamic therapy (MAL-PDT), and to assess what impact the treatment has on promoting remodeling of the photo-damaged skin. Methods Seven patients were enrolled on a clinical trial to assess the effect of MAL-PDT with biopsies taken at screening prior to the first treatment session (week 1), and six weeks after completion of final treatment (week 18). Whole-genome gene expression analysis was carried out on skin biopsies isolated from an AK lesion, an area surrounding the lesion, and a non-sun exposed region of the body. Quantitative PCR was utilized to confirm the differential expression of key genes. Results MAL-PDT treatment corrected abnormal proliferation-related gene profiles, corrected aberrantly expressed cancer-associated genes and induced expression of dermal extracellular matrix genes in photo-exposed skin. Conclusion The efficacy of the MAL-PDT on AK lesions was confirmed at whole-genome gene expression level. A transcriptional signature of remodeling, identified through assessing the effect of MAL-PDT on photodamaged skin, supports the use of MAL-PDT for treating photodamaged skin and field cancerized areas.

Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model.

Targeting IL17 is now an established approach for the treatment of psoriasis. As a key player in this pathway, RORγ has become a major target for the industry leading to a series of new compounds reaching the clinic, with VTP-43742 and GSK2981278 leading the way for oral and topical treatment respectively. As part of our ongoing research on RORγ inverse agonists as new modalities to treat psoriasis, we set out to find compounds highly compatible with topical administration. Starting from known competitor compounds and from our own published assets, the design focused on optimizing the predicted flux through skin while maintaining high potency. This was achieved by carefully reducing lipophilicity of the compounds to achieve good aqueous solubility and eventually lead to the identification of 2 distinct series of potent inverse agonists with promising skin penetration, good solubility in a range of different formulations and robust activity in both the Imiquimod mouse model and a human skin transplant mouse model.

Possible outcomes of acne lesions are atrophic scars, which may cause serious psychological distress. Current treatments for postacne scarring often require invasive procedures. Pathophysiological studies on acne scarring have only investigated the first week of papule life.

First‐ and third‐generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) γ, expressed in the epidermis and infundibulum.

First- and third-generation retinoids even though efficacious in acne, lack full selectivity for RARγ expressed in the epidermis and infundibulum. We describe the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. Trifarotene is a selective RARγ agonist with >20-fold selectivity over RARa and RARβ. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0.01% applied topically is highly comedolytic and has antiinflammatory and antipigmenting properties. Gene expression studies indicated potent activation of known retinoid-modulated processes (epidermal differentiation, proliferation, stress response, RA metabolism) and novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, as well as in human skin after four weeks of topical application of trifarotene 0.005% cream. Based on its RARg selectivity, rapid degradation in human hepatic microsomes and pharmacological properties including potent modulation of epidermal processes, topical treatment with trifarotene could result in good efficacy and may present a favorable safety profile in acne and ichthyotic disorders.

Acne is a chronic inflammatory skin disease, linked to changes in hormone levels. It mainly affects adolescents and young adults, and may lead to permanent scarring. 1.5 billion people aged between 15 and 45 suffer from some form of acne – mild, moderate or severe. Retinoic acid is one type of treatment for acne, and there are several different types, which are applied directly to the skin (topically). Trifarotene is a new type of retinoic acid which is able to act against only one particular retinoic acid receptor, and this study looked at whether it might be suitable for use in acne and other skin diseases, and potentially have an improved efficacy and safety profile compared with less selective retinoids (i.e. ones that target more than one retinoic acid receptor). Looking at the biological pathways of the drug, the authors suggest that it should be very effective in acne. Furthermore, trifarotene is expected to be rapidly eliminated in the blood stream, thereby potentially leading to fewer side effects and making it particularly useful for the treatment of large skin surface areas, such as the back and chest of acne patients. Based on these favourable characteristics of trifarotene, it is worth now investigating the clinical efficacy of this retinoid.

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Overrepresentation of the VKIV subgroup in light chain deposition disease Luc Denoroy, Sophie Déret, Pierre Aucouturier

痤疮是一种慢性炎症性皮肤病,与激素水平变动有关。它主要影响青少年和年轻人,可能导致永久性疤痕。15亿15岁至45岁之间的人群曾患上某种形式的痤疮 ‐ 轻度、中度或重度。视黄酸是痤疮的一类治疗方法,存在多种不同类型,可直接敷用在皮肤上(局部)。Trifarotene是新型视黄酸,能够只针对一种特定的视黄酸受体起作用,而本研究调查了它是否适用于痤疮和其他皮肤疾病,并且与选择性更低的视黄酸(即针对多个视黄酸受体)相比是否可能改善疗效和安全性。通过调查药物的生物学途径,作者表示,该药物应该对痤疮非常有效。此外,trifarotene将在血流中迅速消失,因此可能会减少副作用,使其特别适用于治疗大面积的皮肤表面部位,比如痤疮患者的背部和颈部。基于trifarotene的这些有利特征,此视黄酸的临床效果目前很值得研究。

Rosacea is a common chronic inflammatory skin disease of unknown etiology. Our knowledge about an involvement of the adaptive immune system is very limited. We performed detailed transcriptome analysis, quantitative real-time reverse-transcriptase-PCR, and quantitative immunohistochemistry on facial biopsies of rosacea patients, classified according to their clinical subtype. As controls, we used samples from patients with facial lupus erythematosus and healthy controls. Our study shows significant activation of the immune system in all subtypes of rosacea, characterizing erythematotelangiectatic rosacea (ETR) already as a disease with significant influx of proinflammatory cells. The T-cell response is dominated by Th1/Th17-polarized immune cells, as demonstrated by significant upregulation of IFN-γ or IL-17, for example. Chemokine expression patterns support a Th1/Th17 polarization profile of the T-cell response. Macrophages and mast cells are increased in all three subtypes of rosacea, whereas neutrophils reach a maximum in papulopustular rosacea. Our studies also provide evidence for the activation of plasma cells with significant antibody production already in ETR, followed by a crescendo pattern toward phymatous rosacea. In sum, Th1/Th17 polarized inflammation and macrophage infiltration are an underestimated hallmark in all subtypes of rosacea. Therapies directly targeting the Th1/Th17 pathway are promising candidates in the future treatment of this skin disease.

Acne vulgaris (acne) is a common inflammatory disorder of the cutaneous pilo-sebaceous unit. Here we perform a genome-wide association analysis in the United Kingdom, comparing severe cases of acne (n=1,893) with controls (n=5,132). In a second stage, we genotype putative-associated loci in a further 2,063 acne cases and 1,970 controls. We identify three genome-wide significant associations: 11q13.1 (rs478304, Pcombined=3.23 × 10−11, odds ratio (OR)=1.20), 5q11.2 (rs38055, Pcombined=4.58 × 10−9, OR=1.17) and 1q41 (rs1159268, Pcombined=4.08 × 10−8, OR=1.17). All three loci contain genes linked to the TGFβ cell signalling pathway, namely OVOL1, FST and TGFB2. Transcripts of OVOL1 and TFGB2 have decreased expression in affected compared with normal skin. Collectively, these data support a key role for dysregulation of TGFβ-mediated signalling in susceptibility to acne. Acne vulgarisis a common, inflammatory skin disorder. Here the authors carry out a genome-wide association study and identify three genetic variants that associate with an increased risk of developing acne, which together suggest a mechanistic role for the TGFβ cell signalling pathway in acne development and progression.

The mechanisms of inflammation in acne are currently subject of intense investigation. This study focused on the activation of adaptive and innate immunity in clinically early visible inflamed acne lesions and was performed in two independent patient populations. Biopsies were collected from lesional and non-lesional skin of acne patients. Using Affymetrix Genechips, we observed significant elevation of the signature cytokines of the Th17 lineage in acne lesions compared to non-lesional skin. The increased expression of IL-17 was confirmed at the RNA and also protein level with real-time PCR (RT-PCR) and Luminex technology. Cytokines involved in Th17 lineage differentiation (IL-1β, IL-6, TGF-β, IL23p19) were remarkably induced at the RNA level. In addition, proinflammatory cytokines and chemokines (TNF-α, IL-8, CSF2 and CCL20), Th1 markers (IL12p40, CXCR3, T-bet, IFN-γ), T regulatory cell markers (Foxp3, IL-10, TGF-β) and IL-17 related antimicrobial peptides (S100A7, S100A9, lipocalin, hBD2, hBD3, hCAP18) were induced. Importantly, immunohistochemistry revealed significantly increased numbers of IL-17A positive T cells and CD83 dendritic cells in the acne lesions. In summary our results demonstrate the presence of IL-17A positive T cells and the activation of Th17-related cytokines in acne lesions, indicating that the Th17 pathway is activated and may play a pivotal role in the disease process, possibly offering new targets of therapy.