Sanford-Burnham Medical Research Institute, La Jolla, San Diego, California 92037, USA.
ACS Chem Biol. 2010 Mar 19;5(3):287-99. doi: 10.1021/cb9003089.
Dysregulation of NF-kappaB activity contributes to many autoimmune and inflammatory diseases. At least nine pathways for NF-kappaB activation have been identified, most of which converge on the IkappaB kinases (IKKs). Although IKKs represent logical targets for potential drug discovery, chemical inhibitors of IKKs suppress all known NF-kappaB activation pathways and thus lack the selectivity required for safe use. A unique NF-kappaB activation pathway is initiated by protein kinase C (PKC) that is stimulated by antigen receptors and many growth factor receptors. Using a cell-based high-throughput screening (HTS) assay and chemical biology strategy, we identified a 2-aminobenzimidazole compound, CID-2858522, which selectively inhibits the NF-kappaB pathway induced by PKC, operating downstream of PKC but upstream of IKKbeta, without inhibiting other NF-kappaB activation pathways. In human B cells stimulated through surface immunoglobulin, CID-2858522 inhibited NF-kappaB DNA-binding activity and expression of endogenous NF-kappaB-dependent target gene, TRAF1. Altogether, as a selective chemical inhibitor of the NF-kappaB pathway induced by PKC, CID-2858522 serves as a powerful research tool and may reveal new paths toward therapeutically useful NF-kappaB inhibitors.
NF-κB 活性失调导致许多自身免疫和炎症性疾病。已经确定了至少九条 NF-κB 激活途径，其中大多数途径都集中在 IκB 激酶 (IKK) 上。虽然 IKK 是潜在药物发现的合理靶点，但 IKK 的化学抑制剂抑制了所有已知的 NF-κB 激活途径，因此缺乏安全使用所需的选择性。一种独特的 NF-κB 激活途径是由蛋白激酶 C (PKC) 启动的，PKC 受抗原受体和许多生长因子受体的刺激。我们使用基于细胞的高通量筛选 (HTS) 测定和化学生物学策略，鉴定了一种 2-氨基苯并咪唑化合物 CID-2858522，它选择性地抑制 PKC 诱导的 NF-κB 途径，该途径在 IKKβ的上游但在 PKC 的下游起作用，而不抑制其他 NF-κB 激活途径。在通过表面免疫球蛋白刺激的人 B 细胞中，CID-2858522 抑制 NF-κB DNA 结合活性和内源性 NF-κB 依赖性靶基因 TRAF1 的表达。总之，作为 PKC 诱导的 NF-κB 途径的选择性化学抑制剂，CID-2858522 可作为一种强大的研究工具，可能为具有治疗用途的 NF-κB 抑制剂开辟新途径。
