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This complicates mechanism of action studies, drug repurposing, and development of new therapies. Here, we describe kinome-wide profiling of an optimal kinase library (OKL) comprising 192 small molecules selected based on stage of clinical development, chemical diversity, and target coverage. Our results show that polypharmacology is widespread and independent of regulatory approval. The generally understood (\u201cassigned\u201d) targets of approved molecules are not necessarily the most potently inhibited and off-targets include multiple understudied kinases. Moreover, median selectivity has not increased over time We illustrate how an OKL in combination with detailed kinome profiling can be used to identify potential toxicity targets, repurpose anti-inflammatory drugs for neurodegenerative and infectious diseases, and perform chemical genetic studies. Our studies also highlight how much remains to be discovered about the chemistry and biology of one of the largest classes of human therapeutics.<\/jats:p>","DOI":"10.64898\/2026.03.17.711623","type":"posted-content","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T21:10:21Z","timestamp":1773954621000},"source":"Crossref","is-referenced-by-count":0,"title":["Polypharmacology is an enduring and nearly universal property of kinase inhibitors"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2608-4084","authenticated-orcid":false,"given":"Caitlin E.","family":"Mills","sequence":"first","affiliation":[{"name":"Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, 02115, USA"},{"name":"Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA"},{"name":"Ludwig Centre at Harvard, Harvard Medical School, Boston, MA, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8299-3274","authenticated-orcid":false,"given":"Clemens","family":"Hug","sequence":"additional","affiliation":[{"name":"Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, 02115, USA"},{"name":"Ludwig Centre at Harvard, Harvard Medical School, Boston, MA, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9093-3845","authenticated-orcid":false,"given":"Karuna Anna","family":"Sajeevan","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0105-9605","authenticated-orcid":false,"given":"Nicholas","family":"Clark","sequence":"additional","affiliation":[{"name":"Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, 02115, USA"},{"name":"Department of Host-Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9002-1328","authenticated-orcid":false,"given":"Chiara","family":"Victor","sequence":"additional","affiliation":[{"name":"Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, 02115, USA"},{"name":"Lyell Immunopharma, Inc., Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4033-7930","authenticated-orcid":false,"given":"Mirra","family":"Chung","sequence":"additional","affiliation":[{"name":"Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9618-2153","authenticated-orcid":false,"given":"Sameer","family":"Rawat","sequence":"additional","affiliation":[{"name":"Khoury College of Computer Sciences, Northeastern University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5714-7724","authenticated-orcid":false,"given":"Hope","family":"D\u2019Erasmo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine and Stuart B. 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