CAS: 314054-00-7; N-(4-Iodophenyl)-5-Nitrofuran-2-Carboxamide

专利信息

专利号:US-2022249426-A1
优先权日:2019-07-24
标题:Inhibitors of the sting pathway for the treatment of hidradenitis suppurativa
发明人：LEVY YVES; HUE SOPHIE; FRANCETTE JEAN-LOUIS; ORVAIN CINDY
权利人:INSERM INSTITUT NAT DE LA SANTE ET DE LA RECHERCH MEDICALE; HOPITAUX PARIS ASSIST PUBLIQUE; UNIV PARIS VAL DE MARNE
摘要:Hidradenitis suppurativa (HS) is a chronic, relapsing, inflammatory skin disease in which the primary abnormality appears to affect the pilosebaceous-apocrine unit. Here, inventors' objective was to characterize the molecular mechanisms involved in the pro-inflammatory phenotype of HS-ORS cells. Transcriptomic analyses of HS-ORS cells demonstrated dysregulation of genes involved in cell proliferation and differentiation, as well as upregulation of the DNA damage response (DDR) and IFN signature. The inventors identified abnormalities in the HF-SC compartment from patients with HS, including high counts of proliferating progenitor cells and loss of quiescent bulge stem cells. Fork progression analysis revealed replicative stress responsible for ATR-CHK1 pathway activation. Accumulation of ssDNA and micronuclei in the cytosol of HS-ORS cells was found to contribute to STING activation via the DNA sensor IF116, inducing IFN synthesis independently of cGAS. STING depletion in ORS cells resulted in modulation of fork progression. These findings support the concept that, in patients with HS, impaired HF-SC homeostasis responsible for increased proliferation induces replicative stress and cytosolic ssDNA accumulation, thereby stimulating IFN synthesis through the STING pathway. Accordingly, inhibiting said pathway would be suitable of the treatment of HS.