{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T08:45:43Z","timestamp":1792140343921,"version":"4.4.0"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Akt is a central serine\/threonine kinase in the PI3K\/Akt\/mTOR pathway that regulates cell survival, growth, and metabolic homeostasis. Although Akt1, Akt2, and Akt3 share high sequence homology, they perform distinct physiological and pathological functions, motivating the development of small-molecule isoform-selective chemical probes. Here, we first applied a molecular hybridization strategy to combine structural features that lead to Akt3-selectivity with the covalent pharmacophore of established covalent-allosteric Akt inhibitors, enabling selective and covalent targeting of Akt3. We then expanded the chemical space of covalent-allosteric Akt inhibitors to investigate how subtle structural differences influence selectivity across all three isoforms. Guided by structure\u2013activity relationships and high-resolution co-crystal structures, systematic modifications of substituent patterns, linker geometry, and scaffold architecture revealed distinct isoform-selectivity profiles. Biochemical target inhibition, cellular target engagement, and covalent-binding studies further characterized these compounds and their selectivity. Collectively, these findings expand the covalent-allosteric Akt inhibitor toolbox, provide insight into the structural determinants governing Akt isoform selectivity, and establish molecular hybridization as a strategy for selective covalent targeting of Akt3.<\/jats:p>","DOI":"10.1021\/acschembio.6c00415","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:02:21Z","timestamp":1790672541000},"page":"2572-2596","source":"Crossref","is-referenced-by-count":0,"title":["Covalent-Allosteric Akt Inhibitors: Targeting Akt3 through Molecular Hybridization and Expanding the Isoform-Selective Toolbox"],"prefix":"10.1021","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6532-1624","authenticated-orcid":true,"given":"Kosmas Alexandros","family":"Pervanidis","sequence":"first","affiliation":[{"name":"TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum f\u00fcr Integrierte Wirkstoffforschung (ZIW) , , Otto-Hahn-Str. 4a , ,","place":["Dortmund, Germany, 44227"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5038-3865","authenticated-orcid":true,"given":"Giovanni Danilo","family":"D\u2019Angelo","sequence":"additional","affiliation":[{"name":"TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum f\u00fcr Integrierte Wirkstoffforschung (ZIW) , , Otto-Hahn-Str. 4a , ,","place":["Dortmund, Germany, 44227"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Athanasiadis","sequence":"additional","affiliation":[{"name":"TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum f\u00fcr Integrierte Wirkstoffforschung (ZIW) , , Otto-Hahn-Str. 4a , ,","place":["Dortmund, Germany, 44227"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Jantzen","sequence":"additional","affiliation":[{"name":"TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum f\u00fcr Integrierte Wirkstoffforschung (ZIW) , , Otto-Hahn-Str. 4a , ,","place":["Dortmund, Germany, 44227"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2760-611X","authenticated-orcid":true,"given":"Andrea","family":"Scrima","sequence":"additional","affiliation":[{"name":"TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum f\u00fcr Integrierte Wirkstoffforschung (ZIW) , , Otto-Hahn-Str. 4a , ,","place":["Dortmund, Germany, 44227"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum f\u00fcr Integrierte Wirkstoffforschung (ZIW) , , Otto-Hahn-Str. 4a , ,","place":["Dortmund, Germany, 44227"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Quambusch","sequence":"additional","affiliation":[{"name":"TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum f\u00fcr Integrierte Wirkstoffforschung (ZIW) , , Otto-Hahn-Str. 4a , ,","place":["Dortmund, Germany, 44227"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1529-8933","authenticated-orcid":true,"given":"Matthias P.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum f\u00fcr Integrierte Wirkstoffforschung (ZIW) , , Otto-Hahn-Str. 4a , ,","place":["Dortmund, Germany, 44227"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1970-7642","authenticated-orcid":true,"given":"Daniel","family":"Rauh","sequence":"additional","affiliation":[{"name":"TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum f\u00fcr Integrierte Wirkstoffforschung (ZIW) , , Otto-Hahn-Str. 4a , ,","place":["Dortmund, Germany, 44227"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"issue":"8","key":"2026101523063027600_cit1","doi-asserted-by":"publisher","first-page":"6052","DOI":"10.1021\/acs.jmedchem.4c00075","article-title":"Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises","volume":"67","author":"Pervanidis","year":"2024","journal-title":"J. Med. Chem."},{"issue":"1","key":"2026101523063027600_cit2","doi-asserted-by":"publisher","first-page":"15715","DOI":"10.1038\/s41598-022-20208-5","article-title":"Identification and development of a subtype-selective allosteric AKT inhibitor suitable for clinical development","volume":"12","author":"Page","year":"2022","journal-title":"Sci. Rep."},{"key":"2026101523063027600_cit3","doi-asserted-by":"publisher","first-page":"W375","DOI":"10.1093\/nar\/gkm216","article-title":"MolProbity: all-atom contacts and structure validation for proteins and nucleic acids","volume":"35","author":"Davis","year":"2007","journal-title":"Nucleic Acids Res."},{"issue":"1","key":"2026101523063027600_cit4","doi-asserted-by":"publisher","DOI":"10.1101\/mcs.a004549","article-title":"Clinical report: one year of treatment of Proteus syndrome with miransertib (ARQ 092)","volume":"6","author":"Biesecker","year":"2020","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"issue":"13","key":"2026101523063027600_cit5","doi-asserted-by":"publisher","first-page":"6455","DOI":"10.1021\/acs.jmedchem.6b00619","article-title":"Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor","volume":"59","author":"Lapierre","year":"2016","journal-title":"J. Med. Chem."},{"issue":"35","key":"2026101523063027600_cit6","doi-asserted-by":"publisher","first-page":"10313","DOI":"10.1002\/anie.201502142","article-title":"Covalent-Allosteric Kinase Inhibitors","volume":"54","author":"Weisner","year":"2015","journal-title":"Angew. Chem., Int. Ed. 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Cell Melanoma Res."},{"issue":"Pt 6","key":"2026101523063027600_cit16","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1093\/brain\/awv045","article-title":"PI3K\/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia","volume":"138","author":"Jansen","year":"2015","journal-title":"Brain"},{"issue":"20","key":"2026101523063027600_cit17","doi-asserted-by":"publisher","first-page":"14032","DOI":"10.1021\/acs.jmedchem.2c01246","article-title":"Discovery of Isoform-Selective Akt3 Degraders Overcoming Osimertinib-Induced Resistance in Non-Small Cell Lung Cancer Cells","volume":"65","author":"Xu","year":"2022","journal-title":"J. Med. 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