Rho kinase inhibitor

Rho kinase inhibitors (rho-associated protein kinase inhibitor or ROCK inhibitor) are a series of compounds that target rho kinase (ROCK). Clinical trials have found that inhibition of the ROCK pathway contributes to the cardiovascular benefits of statin therapy. Furthermore, ROCK inhibitors may have clinical applications for anti-erectile dysfunction, antihypertension, and tumor metastasis inhibition.[1] More recently they have been studied for the treatment of glaucoma[2] and as a therapeutic target for the treatment of cardiovascular diseases, including ischemic stroke.[3] While statin therapy has been demonstrated to reduce the risk of major cardiovascular events, including ischemic stroke,[4] the interplay between the ROCK pathway and statin therapy to treat and prevent strokes in older adults has not yet been proven.[3]

On a cellular level ROCK has multiple functions, including regulation of smooth muscle cell contraction, cell migration, and maintenance of cell viability and morphology, in part by regulating stress fibers and focal adhesions.[1] Particularly, ROCK inhibitor is used for cell culture practice, in part to limit cellular death and limited dedifferentiation,[5][6][7] and therefore widely adopted for induced pluripotent stem cells (iPSC) and embryonic stem cell cultures,[8] although studies have shown mixed results for other cells types.[9]

Examples

A number of Rho kinase inhibitors are known.[10][11]

Chemical structure of fasudil
  • AT-13148 [12]
  • BA-210
  • β-Elemene
  • DJ4, which is a selective multi-specific ATP competitive inhibitor of activity of ROCK1 (IC50 of 5 nM), ROCK2 (IC50 of 50 nM), MRCKα (IC50 of 10 nM) and MRCKβ (IC50 of 100 nM) kinases without affecting activity of PAK1 and DMPK at 5 μM concentrations in in vitro cell-free kinase activity assays.[13] DJ4 reduces stress fiber formation, and inhibits migration and invasion of melanoma (A375), breast (MD-MB-231), and non-small cell lung cancer (A549) cells independent of cell death induction.
  • Fasudil, not currently approved by the U.S. Food and Drug Administration (FDA), but in Japan and China it is used for improvement and prevention of cerebral vasospasm and the cerebral ischemic symptoms subsequent to subarachnoid hemorrhage surgery.
  • GSK-576371 [14]
  • GSK429286A, C21H16F4N4O2[15]
  • H-1152
  • Hydroxyfasudil, an active metabolite of fasudil
  • Ibuprofen
  • LX-7101 [16]
  • Netarsudil, approved in United States for glaucoma and ocular hypertension.[17]
  • RKI-1447, a potent small molecule inhibitor of ROCK1 and ROCK2.[18] Studies show that RKI-1447 could have anti-invasive and anti-tumor activities.
  • Ripasudil, used in Japan for the treatment of glaucoma and ocular hypertension.
  • TCS-7001
  • Thiazovivin
  • Verosudil (AR-12286) [19]
  • Y-27632, the first small molecule ROCK inhibitor. It selectively inhibits ROCK1 with Ki of 140 nM.[20]
  • Y-30141
  • Y-33075
  • Y-39983

References
  1. Liao JK, Seto M, Noma K (July 2007). "Rho kinase (ROCK) inhibitors". Journal of Cardiovascular Pharmacology. 50 (1): 17–24. doi:10.1097/FJC.0b013e318070d1bd. PMC 2692906. PMID 17666911.
  2. Wang SK, Chang RT (2014). "An emerging treatment option for glaucoma: Rho kinase inhibitors". Clinical Ophthalmology. 8: 883–90. doi:10.2147/OPTH.S41000. PMC 4025933. PMID 24872673.
  3. Sladojevic N, Yu B, Liao JK (December 2017). "ROCK as a therapeutic target for ischemic stroke". Expert Review of Neurotherapeutics. 17 (12): 1167–1177. doi:10.1080/14737175.2017.1395700. PMC 6221831. PMID 29057688.
  4. O'Brien EC, Greiner MA, Xian Y, Fonarow GC, Olson DM, Schwamm LH, et al. (October 2015). "Clinical Effectiveness of Statin Therapy After Ischemic Stroke: Primary Results From the Statin Therapeutic Area of the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) Study". Circulation. 132 (15): 1404–13. doi:10.1161/CIRCULATIONAHA.115.016183. PMID 26246175. S2CID 11252336.
  5. Matsumoto E, Furumatsu T, Kanazawa T, Tamura M, Ozaki T (March 2012). "ROCK inhibitor prevents the dedifferentiation of human articular chondrocytes". Biochemical and Biophysical Research Communications. 420 (1): 124–9. doi:10.1016/j.bbrc.2012.02.127. PMID 22405765.
  6. Furumatsu T, Matsumoto-Ogawa E, Tanaka T, Lu Z, Ozaki T (April 2014). "ROCK inhibition enhances aggrecan deposition and suppresses matrix metalloproteinase-3 production in human articular chondrocytes". Connective Tissue Research. 55 (2): 89–95. doi:10.3109/03008207.2013.852544. PMID 24111521.
  7. Qi Y, Liang X, Dai F, Guan H, Sun J, Yao W (July 2020). "RhoA/ROCK Pathway Activation is Regulated by AT1 Receptor and Participates in Smooth Muscle Migration and Dedifferentiation via Promoting Actin Cytoskeleton Polymerization". International Journal of Molecular Sciences. 21 (15): 5398. doi:10.3390/ijms21155398. PMC 7432407. PMID 32751352.
  8. Claassen DA, Desler MM, Rizzino A (August 2009). "ROCK inhibition enhances the recovery and growth of cryopreserved human embryonic stem cells and human induced pluripotent stem cells". Molecular Reproduction and Development. 76 (8): 722–32. doi:10.1002/mrd.21021. PMC 3257892. PMID 19235204.
  9. Nukaga T, Sakai D, Schol J, Suyama K, Nakai T, Hiyama A, Watanabe M (2019). "Minimal Sustainability of Dedifferentiation by ROCK Inhibitor on Rat Nucleus Pulposus Cells In Vitro". Spine Surgery and Related Research. 3 (4): 385–391. doi:10.22603/ssrr.2019-0019. PMC 6834460. PMID 31768460.
  10. Luo M, Li YQ, Lu YF, Wu Y, Liu R, Zheng YR, Yin M (November 2020). "Exploring the potential of RhoA inhibitors to improve exercise-recoverable spinal cord injury: A systematic review and meta-analysis". Journal of Chemical Neuroanatomy. 111: 101879. doi:10.1016/j.jchemneu.2020.101879. PMID 33197553.
  11. de Sousa GR, Vieira GM, das Chagas PF, Pezuk JA, Brassesco MS (October 2020). "Should we keep rocking? Portraits from targeting Rho kinases in cancer". Pharmacological Research. 160: 105093. doi:10.1016/j.phrs.2020.105093. PMID 32726671.
  12. Rath N, Munro J, Cutiongco MF, Jagiełło A, Gadegaard N, McGarry L, et al. (June 2018). "Rho Kinase Inhibition by AT13148 Blocks Pancreatic Ductal Adenocarcinoma Invasion and Tumor Growth". Cancer Research. 78 (12): 3321–3336. doi:10.1158/0008-5472.CAN-17-1339. PMID 29669760.
  13. Kale VP, Hengst JA, Desai DH, Dick TE, Choe KN, Colledge AL, et al. (November 2014). "A novel selective multikinase inhibitor of ROCK and MRCK effectively blocks cancer cell migration and invasion". Cancer Letters. 354 (2): 299–310. doi:10.1016/j.canlet.2014.08.032. PMC 4182185. PMID 25172415.
  14. Phrommintikul A, Tran L, Kompa A, Wang B, Adrahtas A, Cantwell D, et al. (April 2008). "Effects of a Rho kinase inhibitor on pressure overload induced cardiac hypertrophy and associated diastolic dysfunction". American Journal of Physiology. Heart and Circulatory Physiology. 294 (4): H1804-14. doi:10.1152/ajpheart.01078.2007. PMID 18245565.
  15. GSK429286A@pubchem
  16. Boland S, Bourin A, Alen J, Geraets J, Schroeders P, Castermans K, et al. (September 2015). "Design, synthesis and biological characterization of selective LIMK inhibitors". Bioorganic & Medicinal Chemistry Letters. 25 (18): 4005–10. doi:10.1016/j.bmcl.2015.07.009. PMID 26233434.
  17. "RHOPRESSA presribing information" (PDF). U.S. Food and Drug Administration.
  18. Patel RA, Forinash KD, Pireddu R, Sun Y, Sun N, Martin MP, et al. (October 2012). "RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer". Cancer Research. 72 (19): 5025–34. doi:10.1158/0008-5472.CAN-12-0954. PMC 3463757. PMID 22846914.
  19. Williams RD, Novack GD, van Haarlem T, Kopczynski C (November 2011). "Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension". American Journal of Ophthalmology. 152 (5): 834–41.e1. doi:10.1016/j.ajo.2011.04.012. PMID 21794845.
  20. "information of different kinds of ROCK inhibitor". selleckchemicals.

Further reading
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