1 型 IFN 表达在先天免疫反应中至关重要，但异常表达与自身免疫和癌症相关。在这里，我们鉴定出 N-[4-(1H46 吡唑并[3,4-b] 吡嗪-6-基)-苯基]-磺酰胺 (Sanofi-14h)，这是一种优先抑制 AGC 家族激酶 SGK3 的化合物，如下所示一种 Ifnb1 基因表达的抑制剂，响应巨噬细胞的 STING 刺激。 Sanofi-14h 消除了 SGK 活性，还损害了 STING 激活下游关键 TBK1/IRF3 通路的激活，从而阻断了 STING 与 TBK1 的相互作用。在巨噬细胞系中删除 SGK1/3 不会阻止 TBK1/IRF3 激活，但会降低先天免疫反应所需的转录因子（例如 IRF7 和 STAT1）的表达。其他 AGC 激酶抑制剂可阻断 TBK1 和 IRF3 激活，表明对 STING 通路中的关键调节节点有共同作用。这些研究揭示了先天免疫反应中 SGK 依赖性和 SGK 独立机制，并指出了阻止异常 Ifnb1 表达的方法。版权所有 © 2023 Elsevier Ltd。保留所有权利。

Type 1 IFN expression is critical in the innate immune response, but aberrant expression is associated with autoimmunity and cancer. Here, we identify N-[4-(1H46 pyrazolo[3,4-b] pyrazin-6-yl)-phenyl]-sulfonamide (Sanofi-14h), a compound with preference for inhibition of the AGC family kinase SGK3, as an inhibitor of Ifnb1 gene expression in response to STING stimulation of macrophages. Sanofi-14h abrogated SGK activity and also impaired activation of the critical TBK1/IRF3 pathway downstream of STING activation, blocking interaction of STING with TBK1. Deletion of SGK1/3 in a macrophage cell line did not block TBK1/IRF3 activation but decreased expression of transcription factors, such as IRF7 and STAT1, required for the innate immune response. Other AGC kinase inhibitors blocked TBK1 and IRF3 activation suggesting common action on a critical regulatory node in the STING pathway. These studies reveal both SGK-dependent and SGK-independent mechanisms in the innate immune response and indicate an approach to block aberrant Ifnb1 expression.Copyright © 2023 Elsevier Ltd. All rights reserved.