Rajapaksa Naomi S, Gobbi Alberto, Drobnick Joy, Do Steven, Kolesnikov Aleksandr, Liang Jun, Chen Yongsheng, Sujatha-Bhaskar Swathi, Huang Zhiyu, Brightbill Hans, Francis Ross, Yu Christine, Choo Edna F, DeMent Kevin, Ran Yingqing, An Le, Emson Claire, Maher Jonathan, Wai John, McKenzie Brent S, Lupardus Patrick J, Zarrin Ali A, Kiefer James R, Bryan Marian C
Genentech, Inc., One DNA Way, South San Francisco, California 94080, United States.
WuXi Apptech, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
ACS Med Chem Lett. 2019 Nov 11;11(3):327-333. doi: 10.1021/acsmedchemlett.9b00380. eCollection 2020 Mar 12.
IRAK4 kinase activity transduces signaling from multiple IL-1Rs and TLRs to regulate cytokines and chemokines implicated in inflammatory diseases. As such, there is high interest in identifying selective IRAK4 inhibitors for the treatment of these disorders. We previously reported the discovery of potent and selective dihydrobenzofuran inhibitors of IRAK4. Subsequent studies, however, showed inconsistent inhibition in disease-relevant pharmacodynamic models. Herein, we describe application of a human whole blood assay to the discovery of a series of benzolactam IRAK4 inhibitors. We identified potent molecule that achieves robust in vivo inhibition of cytokines relevant to human disease.
IRAK4激酶活性将来自多种白细胞介素-1受体（IL-1Rs）和Toll样受体（TLRs）的信号进行转导，以调节与炎症性疾病相关的细胞因子和趋化因子。因此，人们对鉴定用于治疗这些疾病的选择性IRAK4抑制剂有着浓厚的兴趣。我们之前报道了强效且选择性的IRAK4二氢苯并呋喃抑制剂的发现。然而，后续研究表明在疾病相关的药效学模型中抑制作用不一致。在此，我们描述了一种人全血分析方法在一系列苯并内酰胺IRAK4抑制剂发现中的应用。我们鉴定出了强效分子，该分子在体内对与人类疾病相关的细胞因子具有强大的抑制作用。
