Rho-associated coiled-coil-containing kinases (ROCKs), serine/threonine protein kinases, were initially identified as downstream targets of the small GTP-binding protein Rho. Pulmonary fibrosis (PF) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Interestingly, ROCK activation has been demonstrated in PF patients and in animal PF models, making it a promising target for PF treatment. Many ROCK inhibitors have been discovered, and four of these have been approved for clinical use; however, no ROCK inhibitors are approved for the treatment of PF patients. In this article, we describe ROCK signaling pathways and the structure-activity relationship, potency, selectivity, binding modes, pharmacokinetics (PKs), biological functions, and recently reported inhibitors of ROCKs in the context of PF. We will also focus our attention on the challenges to be addressed when targeting ROCKs and discuss the strategy of ROCK inhibitor use in the treatment of PF.

06 Jan 2016·Combinatorial Chemistry & High Throughput ScreeningQ4 · MEDICINE

An Integrated In Silico Method to Discover Novel Rock1 Inhibitors: Multi- Complex-Based Pharmacophore, Molecular Dynamics Simulation and Hybrid Protocol Virtual Screening

Q4 · MEDICINE

Article

Author: Li, Sijia ; Chen, Haining ; Tong, Rongsheng ; Hu, Yajiao ; Chen, Guo ; Jiang, Qinglin ; Cai, Lulu ; Zang, Zhihe

Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) is an important regulator of focal adhesion, actomyosin contraction and cell motility. In this manuscript, a combination of the multi-complex-based pharmacophore (MCBP), molecular dynamics simulation and a hybrid protocol of a virtual screening method, comprised of multipharmacophore- based virtual screening (PBVS) and ensemble docking-based virtual screening (DBVS) methods were used for retrieving novel ROCK1 inhibitors from the natural products database embedded in the ZINC database. Ten hit compounds were selected from the hit compounds, and five compounds were tested experimentally. Thus, these results may provide valuable information for further discovery of more novel ROCK1 inhibitors.

01 Jan 2016·Medicinal Chemistry Research

Selective inhibition of ROCK kinase isoforms to promote neuroregeneration after brain surgery

Author: Peng Wang ; Qiuping Shao ; Wenqin Zhou ; Yong Yang

The Rho-associated protein kinase (ROCK) is an essential regulator of Rho signaling pathways in a variety of cellular processes, which has been established as a potential therapeutic target to promote neuroregeneration after brain surgery.The kinase family contains two highly homologous, tissue-specific isoforms ROCK1 and ROCK2, and selective inhibition of them would result in distinct biol. effects in neurotherapy.The two kinase isoforms have only a slight difference across their active sites, but structural components out of the sites seem to confer exquisite specificity for selective binding of inhibitor ligands to ROCK1 and ROCK2.Here, a quant. structure-selectivity relationship model is developed to characterize the relative contribution of each kinase residue to inhibitor selectivity.The model was then used to screen against a panel of known kinase inhibitors, from which five compounds with high theor. selectivity are tested in vitro using a kinase assay protocol to determine their biol. activity and selectivity.Consequently, the compound CAY10576 is found to have moderate and high inhibitory potencies against ROCK1 and ROCK2 (IC₅₀ = 1.8 and 0.04 μM, resp.) as well as strong selectivity between the two isoforms (S = -1.65), which could be considered as a good lead entity to develop potent, selective ROCK inhibitors to promote neurogenesis and neuroregeneration.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	H. Lee Moffitt Cancer Center & Research Institute, Inc.	11 Feb 2013

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