{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T16:42:36Z","timestamp":1781628156624,"version":"3.54.5"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Motivated by the anti\u2010leukemic synergy between histone deacetylase (HDAC) inhibitors and the FDA\u2010approved BCL\u20102 inhibitor venetoclax, coupled with our interests in polypharmacology, we sought to bolster the anti\u2010leukemic efficacy of the clinical drug by grafting HDAC1\u2010selective or HDAC6\u2010selective inhibitor motifs onto a solvent\u2010accessible domain of venetoclax. We discovered multiple polypharmacological agents that both retained the potent BCL\u20102 inhibitory activity of venetoclax and effectively inhibited either HDAC1 or HDAC6 with excellent (up to 80\u2010fold) selectivities for the desired HDAC isoform. In addition, relative to parental venetoclax, two of our lead compounds,\n                    <jats:bold>BD\u20104\u2010213<\/jats:bold>\n                    and\n                    <jats:bold>AMC\u20104\u2010154<\/jats:bold>\n                    , exhibited superior activities against the acute myeloid leukemia cell line MV4;11 and an MV4;11 cell line engineered to overexpress BCL\u20102. Annexin\u2010V assay results confirmed an on\u2010target mechanism of apoptosis for these novel chimeric molecules. Efforts to further boost the HDAC1 or HDAC6 binding affinities and\/or selectivities proved unsuccessful due to synthetic chemistry challenges and solubility problems, which may underscore the difficulties of polypharmacology approaches involving a large inhibitor, such as venetoclax.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70084","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T03:36:25Z","timestamp":1747280185000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Augmenting the Anti\u2010Leukemic Activity of the BCL\u20102 Inhibitor Venetoclax Through Its Transformation Into Polypharmacologic Dual BCL\u20102\/HDAC1 and Dual BCL\u20102\/HDAC6 Inhibitors"],"prefix":"10.1002","volume":"86","author":[{"given":"Alexandria M.","family":"Chan","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Maryland School of Pharmacy Baltimore 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