Rho kinase inhibitor

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Rho-kinase inhibitors (rho-associated protein kinase inhibitor or ROCK inhibitor) are a series of compounds that target rho kinase (ROCK) and inhibit the ROCK pathway. [1] 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. [2] More recently they have been studied for the treatment of glaucoma [3] and as a therapeutic target for the treatment of cardiovascular diseases, including ischemic stroke. [4] While statin therapy has been demonstrated to reduce the risk of major cardiovascular events, including ischemic stroke, [5] the interplay between the ROCK pathway and statin therapy to treat and prevent strokes in older adults has not yet been proven. [4]

Contents

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. [2] Particularly, ROCK inhibitor is used for cell culture practice, in part to limit cellular death and limited dedifferentiation, [6] [7] [8] and therefore widely adopted for induced pluripotent stem cells (iPSC) and embryonic stem cell cultures, [9] although studies have shown mixed results for other cells types. [10]

ROCK Inhibitor Pathway Rhokinase.png
ROCK Inhibitor Pathway

Molecular mechanism

Rho kinase inhibitors act on Rho kinase by altering the conformation of the protein, disrupting translocation to the plasma membrane, preventing ATP-dependent phosphorylation, and blocking RhoA binding to ROCK. [11] Some studies suggest that Rho kinase inhibitors also play a role in anti-angiogenesis by blocking ERK and Akt signaling pathways. [12] [13] Rho kinase inhibitor also functions by blocking rho-mediated dephosphorylation of MLC20. [14]

Examples

A number of Rho kinase inhibitors are known. [15] [16] [17]

Chemical structure of fasudil Fasudil.svg
Chemical structure of fasudil

References

  1. Liao, James K.; Seto, Minoru; Noma, Kensuke (July 2007). "Rho Kinase (ROCK) Inhibitors". Journal of Cardiovascular Pharmacology. 50 (1): 17–24. doi:10.1097/FJC.0b013e318070d1bd. ISSN   0160-2446. PMC   2692906 . PMID   17666911.
  2. 1 2 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.
  3. 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.
  4. 1 2 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.
  5. 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.
  6. 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.
  7. 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. S2CID   41211282.
  8. 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.
  9. 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.
  10. 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.
  11. Yamaguchi, Hiroto; Kasa, Miyuki; Amano, Mutsuki; Kaibuchi, Kozo; Hakoshima, Toshio (2006-03-01). "Molecular Mechanism for the Regulation of Rho-Kinase by Dimerization and Its Inhibition by Fasudil". Structure. 14 (3): 589–600. doi: 10.1016/j.str.2005.11.024 . ISSN   0969-2126. PMID   16531242.
  12. Hata, Yasuaki; Miura, Muneki; Nakao, Shintaro; Kawahara, Shuhei; Kita, Takeshi; Ishibashi, Tatsuro (2008-02-01). "Antiangiogenic properties of fasudil, a potent Rho-Kinase inhibitor" . Japanese Journal of Ophthalmology. 52 (1): 16–23. doi:10.1007/s10384-007-0487-5. ISSN   1613-2246. PMID   18369695. S2CID   179423.
  13. Khalil, Raouf A. (2010). Rho Kinase in Vascular Smooth Muscle. Morgan & Claypool Life Sciences.
  14. Nagumo, Hiromitsu; Sasaki, Yasuharu; Ono, Yoshitaka; Okamoto, Hiroyuki; Seto, Minoru; Takuwa, Yoh (2000-01-01). "Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells". American Journal of Physiology. Cell Physiology. 278 (1): C57 –C65. doi: 10.1152/ajpcell.2000.278.1.C57 . ISSN   0363-6143. PMID   10644512.
  15. You, Y., Zhu, K., Wang, J., Liang, Q., Li, W., Wang, L., ... & Shi, J. (2023). ROCK inhibitor: Focus on recent updates. Chinese Chemical Letters, 108336. https://doi.org/10.1016/j.cclet.2023.108336
  16. 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 . ISSN   0891-0618. PMID   33197553.
  17. 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. S2CID   220877441.
  18. 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 . PMC   6005347 . PMID   29669760.
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  21. 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.
  22. 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. S2CID   6554772.
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  28. 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.
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Further reading