Cellzome AG, Heidelberg, Germany.
Nat Chem Biol. 2012 Apr 29;8(6):576-82. doi: 10.1038/nchembio.957.
We devised a high-throughput chemoproteomics method that enabled multiplexed screening of 16,000 compounds against native protein and lipid kinases in cell extracts. Optimization of one chemical series resulted in CZC24832, which is to our knowledge the first selective inhibitor of phosphoinositide 3-kinase γ (PI3Kγ) with efficacy in in vitro and in vivo models of inflammation. Extensive target- and cell-based profiling of CZC24832 revealed regulation of interleukin-17-producing T helper cell (T(H)17) differentiation by PI3Kγ, thus reinforcing selective inhibition of PI3Kγ as a potential treatment for inflammatory and autoimmune diseases.
我们设计了一种高通量的化学蛋白质组学方法，能够对细胞提取物中的天然蛋白和脂类激酶进行 16000 种化合物的多重筛选。对一个化学系列的优化产生了 CZC24832，据我们所知，它是第一个磷酸肌醇 3-激酶 γ（PI3Kγ）的选择性抑制剂，在炎症的体外和体内模型中都有效。对 CZC24832 的广泛的基于靶标和细胞的分析揭示了 PI3Kγ 对白细胞介素-17 产生的辅助性 T 细胞（T(H)17）分化的调节作用，从而强化了选择性抑制 PI3Kγ 作为治疗炎症和自身免疫性疾病的一种潜在方法。
