A novel 7-phenoxy-benzimidazole derivative as a potent and orally available BRD4 inhibitor for the treatment of melanoma.

The bromodomain-containing protein 4 (BRD4), which is a key epigenetic regulator in cancer, has emerged as an attractive target for the treatment of melanoma. In this study, we investigate 7-phenoxy-benzimidazole derivative 12, which is a novel BRD4 inhibitor for the treatment of melanoma, by performing scaffold hopping on the previously reported benzimidazole derivative 1. Despite their good oral and intravenous exposure, the compounds obtained by modifying derivate 1 exhibit mutagenicity, which was confirmed by the positive Ames test results.

Discovery of a potent, orally available tricyclic derivative as a novel BRD4 inhibitor for melanoma.

The epigenetic regulation of the protein bromodomain-containing protein 4 (BRD4) has emerged as a compelling target for cancer treatment. In this study, we outline the discovery of a novel BRD4 inhibitor for melanoma therapy. Our initial finding was that benzimidazole derivative 1, sourced from our library, was a powerful BRD4 inhibitor.

Role of FK506-sensitive signals in asthmatic lung inflammation.

Asthma is airway inflammatory diseases caused by the activation of group 2 innate lymphoid cells (ILC2s) and type 2 helper T (T2) cells. Cysteine proteases allergen cause tissue damage to airway epithelial cells and activate ILC2-mediated type 2 airway inflammation. FK506 is an immunosuppressive agent against calcium-dependent NFAT activation that is also effective against asthmatic inflammation.

Phthalate ester-induced thymic stromal lymphopoietin mediates allergic dermatitis in mice.

Recently air pollutants and irritants have been labelled as possible exogenous risk factors for allergic disorders. Although the underlying causes of allergic disorders such as atopic dermatitis and asthma remain unclear, the T helper type 2 (Th2) cell-mediated allergic inflammatory cascade may contribute to their pathogenesis. In the last decade, it has been documented that one of the candidates for triggering Th2 commitment is thymic stromal lymphopoietin (TSLP), the expression of which is up-regulated in the lesions of allergic patients.

T-cadherin enhances cell-matrix adhesiveness by regulating beta1 integrin trafficking in cutaneous squamous carcinoma cells.

T-cadherin is a glycosyl-phosphatidylinositol (GPI) anchored cadherin molecule. We previously reported that T-cadherin is normally expressed on the basal keratinocytes of the epidermis and is down-regulated in cutaneous squamous cell carcinoma (SCC). We found that expression of T-cadherin in cutaneous squamous carcinoma cells regulated level of surface beta1 integrin, which functioned as extracellular matrix (ECM) receptor.

T-cadherin negatively regulates the proliferation of cutaneous squamous carcinoma cells.

T-cadherin is a unique member of the cadherin superfamily that lacks the transmembrane and cytoplasmic domains, and is instead linked to the cell membrane via a glycosyl-phosphatidylinositol anchor. We previously reported that T-cadherin was specifically expressed on the basal keratinocytes of the epidermis, and the expression of T-cadherin was significantly reduced in invasive cutaneous squamous cell carcinoma (SCC) and in the lesional skin of psoriasis vulgaris. In this study, to obtain an insight into the role of T-cadherin in keratinocytes, we used transfection methods and examined the effect of overexpression or knockdown of T-cadherin in immortalized keratinocyte cell lines derived from SCC.