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As cell migration is a critical step during metastasis, we assessed the anti\u2010migratory activities of several clinical ALK inhibitors in NSCLC cells and observed differential anti\u2010migratory capabilities despite similar ALK inhibition, with brigatinib displaying superior anti\u2010migratory effects over other ALK inhibitors. Applying an unbiased in\u2005situ mass spectrometry\u2010based chemoproteomics approach, we determined the proteome\u2010wide target profile of brigatinib in <jats:italic>EML4\u2010ALK+<\/jats:italic> NSCLC cells. Dose\u2010dependent and cross\u2010competitive chemoproteomics suggested MARK2 and MARK3 as relevant brigatinib kinase targets. Functional validation showed that combined pharmacological inhibition or genetic modulation of MARK2\/3 inhibited cell migration. Consistently, brigatinib treatment induced inhibitory YAP1 phosphorylation downstream of MARK2\/3. Collectively, our data suggest that brigatinib exhibits unusual cross\u2010phenotype polypharmacology as, despite similar efficacy for inhibiting EML4\u2010ALK\u2010dependent cell proliferation as other ALK inhibitors, it more effectively prevented migration of NSCLC cells due to co\u2010targeting of MARK2\/3.<\/jats:p>","DOI":"10.1002\/cbic.202200766","type":"journal-article","created":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T23:11:33Z","timestamp":1678921893000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Differential Chemoproteomics Reveals MARK2\/3 as Cell Migration\u2010Relevant Targets of the ALK Inhibitor Brigatinib"],"prefix":"10.1002","volume":"24","author":[{"given":"Qianqian","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Drug Discovery H. 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