{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T02:28:43Z","timestamp":1785378523202,"version":"3.55.0"},"reference-count":27,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) with funds from SFB1309","award":["325871075\u2013SFB1309"],"award-info":[{"award-number":["325871075\u2013SFB1309"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Selective and potent inhibitors of the NAD+-dependent deacetylase Sirt2 represent a valuable epigenetic strategy for the treatment of currently incurable diseases such as Parkinson\u2019s disease, Huntington\u2019s disease, Alzheimer\u2019s disease, and multiple sclerosis. Guided by molecular docking and MM\/GBSA validation studies, a lead structure-based hybridization strategy was developed, resulting in a series of very effective Sirt2 inhibitors. With RW-93, we present a highly potent and subtype selective Sirt2 inhibitor (IC50 = 16 nM), which as a next generation SirReal-type inhibitor significantly surpasses established Sirt2 inhibitors and contributes to the extension of the current SAR profile. The structural modification strategy employed in this study proved to be highly promising, resulting in the identification of the most potent low-molecular-weight Sirt2 inhibitor reported to date, providing a promising target for further medicinal chemistry-driven SAR studies.<\/jats:p>","DOI":"10.3390\/ijms26209855","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:50:16Z","timestamp":1760107816000},"page":"9855","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Lead Structure-Based Hybridization Strategy Reveals Major Potency Enhancement of SirReal-Type Sirt2 Inhibitors"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4364-0931","authenticated-orcid":false,"given":"Matthias","family":"Frei","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University, Butenandtstr. 5\u201313, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6877-3704","authenticated-orcid":false,"given":"Ricky","family":"Wirawan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University, Butenandtstr. 5\u201313, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0256-7341","authenticated-orcid":false,"given":"Thomas","family":"Wein","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University, Butenandtstr. 5\u201313, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0009-8629","authenticated-orcid":false,"given":"Franz","family":"Bracher","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University, Butenandtstr. 5\u201313, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/nrd3674","article-title":"Epigenetic protein families: A new frontier for drug discovery","volume":"11","author":"Arrowsmith","year":"2012","journal-title":"Nat. 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