ArticleCancer research2012
RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer.
Article in Cancer research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
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Who cites it
78 citing papers in PubMed, 144 citations in OpenAlex.
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- Pan-cancer analysis reveals Rho kinase addiction as a vulnerability of de-differentiated cancer cells.iScience · 2026Article
- Regenerative effects of RKI-1447 on human corneal endothelial cells: a comparative study.BMC ophthalmology · 2026Article
- Identification of tumor-promoting functions of the Homeobox family transcription factor MSX1 in cervical cancer.Cell death discovery · 2026Article
- Rho GTPases in cancer resistance: mechanisms, vulnerabilities, and therapeutic opportunities.Biochemical Society transactions · 2026Review
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- Effect of Rho Kinase Inhibitor RKI-1447 on Dexamethasone-Induced Ocular Hypertension and Its Molecular Mechanisms in Sprague-Dawley Rats.Drug design, development and therapy · 2026Article
- MLC2: Physiological Functions and Potential Roles in Tumorigenesis.Cell biochemistry and biophysics · 2025Review
- Cell blebbing novel therapeutic possibilities to counter metastasis.Clinical & experimental metastasis · 2024Review
- RhoA-ROCK2 signaling possesses complex pathophysiological functions in cancer progression and shows promising therapeutic potential.Cancer cell international · 2024Review
- Non-Muscle Myosin II A: Friend or Foe in Cancer?International journal of molecular sciences · 2024Review
- Structure-Based Drug Design with a Deep Hierarchical Generative Model.Journal of chemical information and modeling · 2024Article
- Matrix stiffness affects tumor-associated macrophage functional polarization and its potential in tumor therapy.Journal of translational medicine · 2024Review
- Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth.Science advances · 2024Article
- Role of Rho-associated kinases and their inhibitor fasudil in neurodegenerative diseases.Frontiers in neuroscience · 2024Review
- The RhoA-ROCK1/ROCK2 Pathway Exacerbates Inflammatory Signaling in Immortalized and Primary Microglia.Cells · 2023Article
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18 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
The Rho-associated kinases ROCK1 and ROCK2 are critical for cancer cell migration and invasion, suggesting they may be useful therapeutic targets. In this study, we describe the discovery and development of RKI-1447, a potent small molecule inhibitor of ROCK1 and ROCK2. Crystal structures of the RKI-1447/ROCK1 complex revealed that RKI-1447 is a Type I kinase inhibitor that binds the ATP binding site through interactions with the hinge region and the DFG motif. RKI-1447 suppressed phosphorylation of the ROCK substrates MLC-2 and MYPT-1 in human cancer cells, but had no effect on the phosphorylation levels of the AKT, MEK, and S6 kinase at concentrations as high as 10 μmol/L. RKI-1447 was also highly selective at inhibiting ROCK-mediated cytoskeleton re-organization (actin stress fiber formation) following LPA stimulation, but does not affect PAK-meditated lamellipodia and filopodia formation following PDGF and Bradykinin stimulation, respectively. RKI-1447 inhibited migration, invasion and anchorage-independent tumor growth of breast cancer cells. In contrast, RKI-1313, a much weaker analog in vitro, had little effect on the phosphorylation levels of ROCK substrates, migration, invasion or anchorage-independent growth. Finally, RKI-1447 was highly effective at inhibiting the outgrowth of mammary tumors in a transgenic mouse model. In summary, our findings establish RKI-1447 as a potent and selective ROCK inhibitor with significant anti-invasive and antitumor activities and offer a preclinical proof-of-concept that justify further examination of RKI-1447 suitability as a potential clinical candidate.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.