ROCK

ROCK

The Rho kinase (ROCK) isoforms, ROCK1 and ROCK2, were initially discovered as downstream targets of the small GTP-binding protein Rho. Because ROCKs mediate various important cellular functions such as cell shape, motility, secretion, proliferation, and gene expression, it is likely that this pathway will intersect with other signaling pathways known to contribute to cardiovascular disease. Indeed, ROCKs have already been implicated in the regulation of vascular tone, proliferation, inflammation, and oxidative stress.

An overview of ROCK

The Rho kinase (ROCK), belonging to serine/threonine kinase family, was identified as a key downstream effector of the small GTP-binding protein RhoA decades ago. The ROCK family plays a vital role in a series of fundamental cellular functions including contraction, adhesion, migration and apoptosis, and regulates the organization of actin cytoskeleton. The first ROCK family member was discovered in 1996, which has aroused much attention due to the involvement of ROCK in multiple biological processes.

Major types of ROCK

Till now, there are two isoforms of ROCK confirmed: ROCK1 and ROCK2. Structurally, both of them are composed of a catalytic kinase domain, a Rho-binding domain and a C-terminal pleckstrin-homology, sharing 92% homology in the kinase domain. The experiments on ROCKs-deficient mice showed the functional differences between ROCK1 and ROCK2. ROCK1 is mainly expressed in the lung, liver, spleen, and kidney, circulating inflammatory cells. ROCK2 is prominent in brain, heart and muscle, playing a crucial role in vascular smooth muscle cells.

Inhibition of ROCK

The over-expression of ROCK is observed in numerous diseases, which means inhibition of ROCK may show beneficial effect in the treatment of these diseases. According to chemical classification, a series of ROCK inhibitors have been reported including isoquinolines, pyridines, indazoles, pyrazoles. HA1077, also named fasudil, is the first and only clinically available ROCK inhibitor, exerting function by targeting ATP-dependent kinase domain. Pyrides Y-23632 was demonstrated to inhibit smooth muscle contractility and normalized blood pressure by competing with ATP for binding to catalytic sites. Clark et al have found a series of dihydropyrimidine inhibitors of ROCK1 with high selectivity and potency.

ROCK and diseases

Accumulating evidences have indicated that the overexpression of ROCK is involved in the pathogenesis of many diseases such as cardiovascular diseases, nervous system disorders, cancer, diabetes complications. Therefore, ROCK inhibitors show a promising outlook on the treatment of these diseases.

References:

Guan, R. et al. Advances in the studies of roles of Rho/Rho-kinase in diseases and the development of its inhibitors. European Journal of Medicinal Chemistry 70, 613-622 (2013).

LeiWei, MichelleSurma, StephanieShi, NathanLambert-Cheatham & JianjianShi. Novel Insights into the Roles of Rho Kinase in Cancer.

Shimokawa, H., Sunamura, S. & Satoh, K. RhoA/Rho-Kinase in the Cardiovascular System. Circulation Research 118, 352 (2016).

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