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KPT-9274, a clinical stage compound, has been reported as a dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT), but its structural basis has remained undefined. Here, we present high-resolution crystal structures of PAK4 and NAMPT in complex with KPT-7523, an analog of KPT-9274, determined at 2.20 and 1.45\u2005\u00c5 resolution, respectively. In PAK4, the 2-aminopyridine moiety of KPT-7523 enables dual binding, occupying the adenine-binding site for ATP and simultaneously engaging the substrate-binding cleft in the C-lobe, thereby interfering with both catalytic and regulatory functions. In NAMPT, the same scaffold inserts into the NAD\n                    <jats:sup>+<\/jats:sup>\n                    active site in an extended conformation that preserves critical interactions. Biophysical assays revealed distinct affinities across the two targets. These findings highlight the 2-aminopyridine moiety as a versatile pharmacophore that is adaptable to structurally unrelated proteins and provide a framework for designing next-generation dual inhibitors in cancer therapy.\n                  <\/jats:p>","DOI":"10.1107\/s2059798326006145","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T10:58:01Z","timestamp":1784113081000},"page":"972-981","update-policy":"https:\/\/doi.org\/10.1107\/cm_01","source":"Crossref","is-referenced-by-count":0,"title":["Structural basis for a p21-activated kinase 4 and nicotinamide phosphoribosyltransferase dual inhibitor"],"prefix":"10.1107","volume":"82","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1791-8937","authenticated-orcid":true,"given":"Jaehui","family":"Park","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02wnxgj78","id-type":"ROR","asserted-by":"publisher"}],"department":["College of 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