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CC-90001 is a Selective and Orally Active Inhibitor of JNK
2021-03-10

c-Jun N-terminal kinases (JNK) belong to the mitogen-activated protein kinase (MAPK) family, and are responsive for stress stimuli. They also play a critical role in T cell differentiation and apoptosis. Besides, JNK 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 epithelial-mesenchymal transition (EMT). JNK1 also promotes wnt-3-induced EMT by regulating β-Catenin. Furthermore, JNK1 contributes to the production of extracellular matrix (ECM) proteins, especially laminin and fibronectin, in basal cells stimulated by TGFβ1.

Inflammatory signals, such as reactive oxygen species (ROS), ultraviolet radiation, protein synthesis inhibitors and various stress stimuli, can activate JNK. Meanwhile, specific phosphatases usually inhibit the activity of JNK as well as 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.

CC-90001 (HY-138304) is a potent, selective, and orally active JNK1 inhibitor.

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 (IPF). Particularly, CC-90001 blocks the JNK phosphorylation induced by LPS with an EC50 of 480 nM.

Secondly, CC-90001 (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.

Keywords

Fibrogenesis, anti-fibrotic, fibronectin, collagen, α-smooth muscle actin (α-SMA ECM, EMT, oral, steatohepatitis model