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Although cysteine was once the primary focus of such efforts, lysine has emerged as another appealing residue for covalent modification, due to its high prevalence within the proteome, functional importance, and low mutation rate. Despite this amino acid's reduced nucleophilicity at physiological pH, rational, structure\u2010based techniques have enabled the identification of inhibitors that exploit the unique protein microenvironment that a given lysine occupies. Strategies to inhibit Hsp90 via covalent modification of Lys58 include the use of\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acyl\u2010\n                    <jats:italic>N<\/jats:italic>\n                    \u2010aryl sulfonamide (ArNASA) warheads and sulfur(VI) fluoride exchange (SuFEx) chemistry, both of which have demonstrated enhanced cellular selectivity and potency. However, such compounds fail to distinguish between the &gt;\u200995% identical nature of the ligand binding sites in cytosolic Hsp90\n                    <jats:italic>\u03b1<\/jats:italic>\n                    and Hsp90\n                    <jats:italic>\u03b2<\/jats:italic>\n                    . In this study, the incorporation of electrophilic warheads onto Hsp90\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010selective inhibitors resulted in compounds that demonstrate favorable binding to Hsp90\n                    <jats:italic>\u03b2<\/jats:italic>\n                    , yet subsequent analyses to confirm covalent modification of Lys58 were inconclusive. Nevertheless, the kinetics of inhibitor binding to the Hsp90 N\u2010terminal ATP\u2010binding pocket were obtained, whereby some compounds exhibited their highest affinity towards Hsp90\n                    <jats:italic>\u03b2<\/jats:italic>\n                    after a 2\u2009h incubation.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70290","type":"journal-article","created":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T22:09:10Z","timestamp":1776031750000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Attempts to Achieve Targeted Covalent Inhibition of Hsp90\n                    <i>\u03b2<\/i>"],"prefix":"10.1111","volume":"107","author":[{"given":"Terin","family":"D'Amico","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, Warren Center for Drug Discovery The University of Notre Dame  Notre Dame Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tyelor S.","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Warren Center for Drug Discovery The University of Notre Dame  Notre Dame Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael A.","family":"Serwetnyk","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Warren Center for Drug Discovery The University of Notre Dame  Notre Dame Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6200-3480","authenticated-orcid":false,"given":"Brian S. 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