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BoNT\u00a0serotype A is responsible for most human botulism cases, and there are no approved therapeutics to treat already intoxicated patients. A growing body of research has demonstrated that BoNT\/A can escape into the central nervous system, and therefore, identification of BoNT\/A inhibitors that can penetrate BBB and neutralize the toxin within intoxicated neurons would be important. We previously identified an FDA\u2010approved, orally bioavailable compound, KX2\u2010391 (Tirbanibulin)\u00a0that inhibits BoNT\/A in motor neuron assays. Recently, a structural analog of KX2\u2010391, KX2\u2010361, has been shown to exhibit good oral bioavailability and cross BBB with high efficiency in mouse experiments. Therefore, in this work, we evaluated the inhibitory effects of KX2\u2010361 against BoNT\/A. Toward this goal, we first evaluated the compound for its effects on cell viability in PC12 cells, via MTT assay, and in mouse embryonic stem cell (mESC)\u2010derived motor neurons, with imaging\u2010based assays. Following, we tested KX2\u2010361 in mESC\u2010derived motor neurons intoxicated with BoNT\/A holotoxin, and the compound exhibited activity against the toxin in both pre\u2010 and post\u2010intoxication conditions. Excitingly, KX2\u2010361 also inhibited BoNT\/A enzymatic component (light chain; LC) in PC12 cells transfected with BoNT\/A LC. Furthermore, our molecular docking analyses suggested that KX2\u2010361 can directly bind to BoNT\/A LC. Medicinal chemistry approaches to develop structural analogs of KX2\u2010361 to increase its efficacy against BoNT\/A may provide a critical lead compound with BBB penetration capacity for drug development efforts against BoNT\/A intoxication.<\/jats:p>","DOI":"10.1002\/ddr.22248","type":"journal-article","created":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T22:27:02Z","timestamp":1724279222000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tirbanibulin (KX2\u2010391) analog KX2\u2010361 inhibits botulinum neurotoxin serotype A mediated SNAP\u201025 cleavage in pre\u2010 and post\u2010intoxication models in cells"],"prefix":"10.1002","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6077-4604","authenticated-orcid":false,"given":"Dilara","family":"Koc","sequence":"first","affiliation":[{"name":"Department of Biological Sciences Middle East Technical University Ankara 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