Discovery of the Selective Protein Kinase C‑θ Kinase Inhibitor, CC-90005

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 (3) 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 (57) was selected for clinical
development.

蛋白激酶C（protein kinase C）的PKC-θ亚型选择性表达于T淋巴细胞（T lymphocyte），在成熟T细胞的T细胞抗原受体（TCR）介导的活化、T细胞增殖以及后续白细胞介素2（IL-2）等细胞因子的释放过程中发挥重要作用。本文报道了一类新型PKC-θ抑制剂的合成及其构效关系（SAR）。通过结构导向设计与探索性构效关系研究相结合的策略，我们确定了初始先导化合物（3）的碱性C4氨基的合适替代基团。基于性质导向的设计思路，我们筛选得到了适当取代的C2基团，从而获得了兼具代谢稳定性与膜通透性的强效类似物，可支持体内实验的开展。凭借优异的广谱激酶选择性、以IL-2表达为评估指标的细胞水平T细胞活化抑制活性、良好的安全性，以及在口服给药的急性和慢性T细胞活化模型中证实的体内疗效，CC-90005（57）被选定进入临床开发。