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Guided by the lead compound belumosudil, a novel series of ROCK2 inhibitors based on a 6\u2010amino\u20102\u2010piperazine pyridine scaffold was designed and synthesized. The Kinase\u2010Glo assay identified compound <jats:bold>14r<\/jats:bold> as the most potent analog, showing an IC<jats:sub>50<\/jats:sub> value of 82.6\u2009nM, which represented a 1.2\u2010fold improvement over belumosudil. Furthermore, the morphology of MDA\u2010MB\u2010231 cells treated with <jats:bold>14r<\/jats:bold> was significantly changed in immunofluorescent staining analysis. Simultaneously, cell scratch experiments showed that <jats:bold>14r<\/jats:bold> inhibited the migration of MDA\u2010MB\u2010231 cells in a dose\u2010dependent manner. Additionally, molecular docking studies elucidated the binding mode of <jats:bold>14r<\/jats:bold> within the ROCK2 ATP pocket, corroborating its nanomolar\u2010level inhibitory activity. In conclusion, <jats:bold>14r<\/jats:bold> showed great potential for further optimization to suppress breast cancer metastasis.<\/jats:p>","DOI":"10.1002\/ardp.70068","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T11:35:03Z","timestamp":1754566503000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rational Design of 6\u2010Amino\u20102\u2010Piperazinylpyridine\u2010Based ROCK2 Inhibitors With Anti\u2010Breast Cancer Metastatic Efficiency"],"prefix":"10.1002","volume":"358","author":[{"given":"Haoran","family":"Chen","sequence":"first","affiliation":[{"name":"Key Laboratory of Structure\u2010Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering Shenyang Pharmaceutical University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Key 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