公开(公告)号：US20160193292A1

公开(公告)日：2016-07-07

申请号：US14911939

申请日：2014-08-08

申请人： THE CURATORS OF THE UNIVERSITY OF MISSOURI

发明人： Mark A. DANIELS

IPC分类号： A61K38/17 ,  A61K47/48 ,  C12N7/00 ,  C07K14/47 ,  C07K14/005

CPC分类号： A61K38/1709 ,  A61K38/00 ,  A61K47/64 ,  C07K7/08 ,  C07K14/005 ,  C07K14/47 ,  C07K2319/00 ,  C07K2319/10 ,  C12N7/00 ,  C12N2740/16322 ,  C12N2740/16371

摘要： Plenty of SII3 (POSH) and INK-interacting protein 1 (JIP-1) function as a multi-protein scaffold network for TCR-mediated JNK1 activation in CD8+ T-cells. Disruption of the POSH/JIP-1 complex led to profound defects in the activation of JNK1, as well as deficient activation or induction of the transcription factors c-Jun, T-bet and Eomesodermin Furthermore, disruption of the POSH/JIP complex in CD8+T-cells resulted in impaired proliferation, decreased cytokine expression and the inability to control tumors. Collectively, these data identify a mechanism for the specific regulation of TCR-dependent JNK1 activation and function that is key for CD8+ T-cell responses. The disclosure describes a group of compounds that individually or in concert target a common set of biological pathways important in T cell function, activation of innate inflammation, ischemic reperfusion injury, HIV release and oncogenesis.

摘要翻译： SII3（POSH）和INK相互作用蛋白1（JIP-1）作为CD8 + T细胞中TCR介导的JNK1激活的多蛋白质支架网络发挥作用。 POSH / JIP-1复合物的破坏导致JNK1激活的深刻缺陷，以及转录因子c-Jun，T-bet和Eomesodermin的活化或诱导缺陷。此外，CD8 / JIP复合物在CD8中的破坏 + T细胞导致增殖受损，细胞因子表达降低，无法控制肿瘤。 总的来说，这些数据确定了TCR依赖性JNK1激活和功能的特异性调节机制，这是CD8 + T细胞应答的关键。 本公开描述了一组化合物，其单独或一致地靶向在T细胞功能中重要的常见生物学途径，激活先天性炎症，缺血再灌注损伤，HIV释放和肿瘤形成。