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J Med Chem. 2021 Aug 26;64(16):11886-11903. doi: 10.1021/acs.jmedchem.1c00388. Epub 2021 Aug 6.
The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead () were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 () was selected for clinical development.
蛋白激酶 C 的 PKC-θ 同工型选择性表达于 T 淋巴细胞，在 T 细胞抗原受体（TCR）触发成熟 T 细胞激活、T 细胞增殖以及随后白介素-2（IL-2）等细胞因子释放的过程中发挥着重要作用。在此，我们报告了一系列新型 PKC-θ 抑制剂的合成和构效关系（SAR）。通过结构导向设计和探索性 SAR 的结合，确定了原始先导化合物（）中 C4 伯胺的合适替代物。基于性质的设计使我们能够鉴定合适取代的 C2 基团，从而获得具有代谢稳定性和渗透性的有效类似物，以支持体内测试。先导化合物 CC-90005（）具有高度的一般激酶选择性、细胞 T 细胞激活抑制作用（通过 IL-2 表达评估）、良好的安全性特征，并在急性和慢性 T 细胞激活模型中通过口服给药显示出体内疗效，因此被选中进行临床开发。
