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Wherein JNK3 is specifically expressed in brain and emerges as therapeutic target, especially for neurodegenerative diseases. However, developing JNK3 selective inhibitors as chemical probes to investigate its therapeutic potential in diseases remains challenging. Here, we adopted the covalent strategy for identifying JNK3\u2010selective covalent inhibitor <jats:bold>JC16I<\/jats:bold>, with high inhibitory activity against JNK3. Despite targeting a conserved cysteine in the vicinity of ATP pocket in JNK family, <jats:bold>JC16I<\/jats:bold> exerted a greater than 160\u2010fold selectivity for JNK3 over JNK1\/2. Importantly, even at low concentration, <jats:bold>JC16I<\/jats:bold> showed enhanced and long\u2010lasting inhibition against cellular JNK3. In addition, its alkyne\u2010containing probe <jats:bold>JC\u2010P1<\/jats:bold> could label JNK3 in SH\u2010SY5Y cell lysate and living cells, with good proteome\u2010wide selectivity. <jats:bold>JC16I<\/jats:bold> selectively suppressed the abnormal activation of JNK3 signaling and sufficiently exhibited neuroprotective effect in Parkinson's diseases (PD) models. Overall, our findings highlight the potential of developing isoform\u2010selective and cell\u2010active JNK3 inhibitors by covalent drug design strategy targeting a conserved cysteine. This work not only provides a valuable chemical probe for JNK3\u2010targeted investigations <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> but also opens new avenues for the treatment of PD.<\/jats:p>","DOI":"10.1002\/anie.202411037","type":"journal-article","created":{"date-parts":[[2024,9,14]],"date-time":"2024-09-14T12:39:02Z","timestamp":1726317542000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Selective Covalent Inhibiting JNK3 by Small Molecules for Parkinson's Diseases"],"prefix":"10.1002","volume":"63","author":[{"given":"Wen","family":"Shuai","sequence":"first","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center Innovation Center of Nursing Research West China Hospital Sichuan University  No.\u200517, Section\u20053, Renmin South Road 610041 Chengdu 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