Opportunities and Challenges for the Development of MRCK Kinases Inhibitors as Potential Cancer Chemotherapeutics
Cytoskeleton organization and dynamics are rapidly regulated by post-translational modifications of key target proteins. Acting downstream of the Cdc42 GTPase, the myotonic dystrophy-related Cdc42-binding kinases MRCKα, MRCKβ, and MRCKγ have recently emerged as important players in cytoskeleton regu...
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| Format: | Article |
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MDPI AG
2023-02-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/4/534 |
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| author | Vanessa M. Ruscetta Taj J. Seaton Aleen Shakeel Stanley N. S. Vasconcelos Russell D. Viirre Marc J. Adler Michael F. Olson |
| author_facet | Vanessa M. Ruscetta Taj J. Seaton Aleen Shakeel Stanley N. S. Vasconcelos Russell D. Viirre Marc J. Adler Michael F. Olson |
| author_sort | Vanessa M. Ruscetta |
| collection | DOAJ |
| description | Cytoskeleton organization and dynamics are rapidly regulated by post-translational modifications of key target proteins. Acting downstream of the Cdc42 GTPase, the myotonic dystrophy-related Cdc42-binding kinases MRCKα, MRCKβ, and MRCKγ have recently emerged as important players in cytoskeleton regulation through the phosphorylation of proteins such as the regulatory myosin light chain proteins. Compared with the closely related Rho-associated coiled-coil kinases 1 and 2 (ROCK1 and ROCK2), the contributions of the MRCK kinases are less well characterized, one reason for this being that the discovery of potent and selective MRCK pharmacological inhibitors occurred many years after the discovery of ROCK inhibitors. The disclosure of inhibitors, such as BDP5290 and BDP9066, that have marked selectivity for MRCK over ROCK, as well as the dual ROCK + MRCK inhibitor DJ4, has expanded the repertoire of chemical biology tools to study MRCK function in normal and pathological conditions. Recent research has used these novel inhibitors to establish the role of MRCK signalling in epithelial polarization, phagocytosis, cytoskeleton organization, cell motility, and cancer cell invasiveness. Furthermore, pharmacological MRCK inhibition has been shown to elicit therapeutically beneficial effects in cell-based and in vivo studies of glioma, skin, and ovarian cancers. |
| first_indexed | 2024-03-11T09:01:22Z |
| format | Article |
| id | doaj.art-d9d3e7e172be471baceb587bc7309f2f |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T09:01:22Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-d9d3e7e172be471baceb587bc7309f2f2023-11-16T19:43:40ZengMDPI AGCells2073-44092023-02-0112453410.3390/cells12040534Opportunities and Challenges for the Development of MRCK Kinases Inhibitors as Potential Cancer ChemotherapeuticsVanessa M. Ruscetta0Taj J. Seaton1Aleen Shakeel2Stanley N. S. Vasconcelos3Russell D. Viirre4Marc J. Adler5Michael F. Olson6Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5B 2K3, CanadaDepartment of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5B 2K3, CanadaDepartment of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5B 2K3, CanadaDepartment of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5B 2K3, CanadaDepartment of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5B 2K3, CanadaDepartment of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5B 2K3, CanadaDepartment of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5B 2K3, CanadaCytoskeleton organization and dynamics are rapidly regulated by post-translational modifications of key target proteins. Acting downstream of the Cdc42 GTPase, the myotonic dystrophy-related Cdc42-binding kinases MRCKα, MRCKβ, and MRCKγ have recently emerged as important players in cytoskeleton regulation through the phosphorylation of proteins such as the regulatory myosin light chain proteins. Compared with the closely related Rho-associated coiled-coil kinases 1 and 2 (ROCK1 and ROCK2), the contributions of the MRCK kinases are less well characterized, one reason for this being that the discovery of potent and selective MRCK pharmacological inhibitors occurred many years after the discovery of ROCK inhibitors. The disclosure of inhibitors, such as BDP5290 and BDP9066, that have marked selectivity for MRCK over ROCK, as well as the dual ROCK + MRCK inhibitor DJ4, has expanded the repertoire of chemical biology tools to study MRCK function in normal and pathological conditions. Recent research has used these novel inhibitors to establish the role of MRCK signalling in epithelial polarization, phagocytosis, cytoskeleton organization, cell motility, and cancer cell invasiveness. Furthermore, pharmacological MRCK inhibition has been shown to elicit therapeutically beneficial effects in cell-based and in vivo studies of glioma, skin, and ovarian cancers.https://www.mdpi.com/2073-4409/12/4/534cytoskeletonsignal transductionphosphorylation |
| spellingShingle | Vanessa M. Ruscetta Taj J. Seaton Aleen Shakeel Stanley N. S. Vasconcelos Russell D. Viirre Marc J. Adler Michael F. Olson Opportunities and Challenges for the Development of MRCK Kinases Inhibitors as Potential Cancer Chemotherapeutics Cells cytoskeleton signal transduction phosphorylation |
| title | Opportunities and Challenges for the Development of MRCK Kinases Inhibitors as Potential Cancer Chemotherapeutics |
| title_full | Opportunities and Challenges for the Development of MRCK Kinases Inhibitors as Potential Cancer Chemotherapeutics |
| title_fullStr | Opportunities and Challenges for the Development of MRCK Kinases Inhibitors as Potential Cancer Chemotherapeutics |
| title_full_unstemmed | Opportunities and Challenges for the Development of MRCK Kinases Inhibitors as Potential Cancer Chemotherapeutics |
| title_short | Opportunities and Challenges for the Development of MRCK Kinases Inhibitors as Potential Cancer Chemotherapeutics |
| title_sort | opportunities and challenges for the development of mrck kinases inhibitors as potential cancer chemotherapeutics |
| topic | cytoskeleton signal transduction phosphorylation |
| url | https://www.mdpi.com/2073-4409/12/4/534 |
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