c-Jun N-terminal kinases (JNKs) belong to the mitogen-activated protein kinase family and are responsive to stress stimuli. Specifically, JNKs belong to the mitogen-activated protein kinase family and respond to stress. They also play a role in T cell differentiation and apoptosis. Besides, C-Jun N-terminal kinase consists of ten isotypes from three genes: JNK1, jnk2, and JNK3. Moreover, JNK1 (but not JNK2) is the main regulator of TGFβ-induced epithelial to mesenchymal transition. JNK1 also promotes wnt-3-induced EMT by regulating β-Catenin. Furthermore, JNK1 contributes to the production of ECM proteins, especially laminin and fibronectin, in basal cells stimulated by TGFβ1.
Inflammatory signals, changes in reactive oxygen species, ultraviolet radiation, protein synthesis inhibitors, and various stress stimuli can activate JNK. Meanwhile, specific phosphatases usually inhibit the activity of JNK itself and the activity of proteins related to JNK activation. Nonetheless, through phosphorylation, JNK modifies the activity of many proteins that exist in mitochondria or function in nucleus. Today, we will introduce a potent, selective, and orally active JNK inhibitor, CC-90001.
CC-90001 is a Selective and Orally Active Inhibitor of JNK.
At first, CC-90001 shows 12.9-fold selectivity for JNK1 over JNK2 in a cell-based model. Importantly, CC-90001 can be used for the research of idiopathic pulmonary fibrosis. Particularly, CC-90001 blocked the c-Jun phosphorylation induced by LPS with an EC50 of 480 nm.
Secondly, CC-90001 with 3 mg/kg b.i.d. reduces the development of fibrosis. Obviously, it has a 48% reduction in collagen and a 53% reduction in α-smooth muscle actin (α-SMA) in a steatohepatitis model. CC-90001 decreases multiple measures of lung collagen. Additionally, CC-90001 reduces disease-induced increases in α-SMA to nearly baseline levels in a house dust mite model of lung fibrosis.
All in all, CC-90001 is a potent, selective, and orally active inhibitor of JNK.