{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:35:07Z","timestamp":1790710507921,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["INST 212\/474\u20101 FUGG"],"award-info":[{"award-number":["INST 212\/474\u20101 FUGG"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["EFRE\u2010800400"],"award-info":[{"award-number":["EFRE\u2010800400"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70115201"],"award-info":[{"award-number":["70115201"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The Akt family of serine\/threonine kinases plays a crucial role in various cellular processes, including proliferation, survival, and metabolism. Three Akt isoforms (Akt1, Akt2, and Akt3) have distinct physiological roles, and while individual isoform dysregulation is disease\u2010linked, unselective Akt inhibition leads to side effects. Here, we report the development of selective covalent\u2010allosteric Akt inhibitors (CAAIs) targeting Akt2 and Akt3 while sparing Akt1. Guided by protein x\u2010ray crystallography and molecular modeling, key structural differences within the allosteric pockets of the isoforms were identified and exploited in a structure\u2010based design strategy. By stabilizing the inactive kinase conformation, CAAIs overcome the intrinsic selectivity limitations of ATP\u2010competitive inhibitors. After biological characterization, the pyrazole\u2010containing inhibitors emerged as the most potent and selective Akt2 inhibitors, while inhibitors with pyridines as an isoform\u2010selective element were predominantly targeting Akt3 selectively. Importantly, these new inhibitors were also evaluated in patient\u2010derived colorectal cancer organoids. Co\u2010crystal structures of inhibitors bound to an engineered construct mimicking the Akt2 allosteric pocket elucidated the molecular basis of isoform selectivity, guiding further optimization. This work not only establishes a framework for the development of isoform\u2010selective therapeutics but also highlights the potential for unraveling isoform\u2010specific functions in signaling pathways relevant to cancer biology.<\/jats:p>","DOI":"10.1002\/anie.3567206","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:58:42Z","timestamp":1788785922000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Isoform\u2010Selective Targeting of Akt Through Covalent Allosteric Inhibition"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5038-3865","authenticated-orcid":false,"given":"Giovanni Danilo","family":"D'Angelo","sequence":"first","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6532-1624","authenticated-orcid":false,"given":"Kosmas Alexandros","family":"Pervanidis","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9893-2910","authenticated-orcid":false,"given":"Ioannis","family":"Athanasiadis","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5252-9757","authenticated-orcid":false,"given":"Vladimir","family":"Lukianchikov","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2760-611X","authenticated-orcid":false,"given":"Andrea","family":"Scrima","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Depta","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Stier","sequence":"additional","affiliation":[{"name":"Institute for Tumor Biology and Experimental Therapy Georg\u2010Speyer\u2010Haus  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1529-8933","authenticated-orcid":false,"given":"Matthias P.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1558-5366","authenticated-orcid":false,"given":"Henner F.","family":"Farin","sequence":"additional","affiliation":[{"name":"Institute for Tumor Biology and Experimental Therapy Georg\u2010Speyer\u2010Haus  Frankfurt am Main Germany"},{"name":"Frankfurt Cancer Institute, Goethe University  Frankfurt am Main Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt\/Mainz and German Cancer Research Center (DKFZ)  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1463-2450","authenticated-orcid":false,"given":"Lena","family":"Quambusch","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1970-7642","authenticated-orcid":false,"given":"Daniel","family":"Rauh","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers10030078"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.009"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST0350231"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102014\u201003\u2010559963"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm301024w"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00075"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201011\u20103321"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010022\u201020208\u20105"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b00619"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201502142"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4103"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1713137"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1215637"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306220"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201909857"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201025512\u20108"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c01488"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.116906"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117334"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.2174\/156802610790980602"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8SC05212C"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.6.5.3995"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2024.08.010"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201023\u20100050"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2002.148"},{"issue":"1","key":"e_1_2_8_27_1","first-page":"S162","article-title":"Automated Comparative Protein Structure Modeling With SWISS\u2010MODEL and Swiss\u2010PdbViewer: A Historical Perspective","volume":"30","author":"Guex N.","year":"2009","journal-title":"Electrophoresis"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1132"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky427"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz828"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904019158"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798319011471"},{"key":"e_1_2_8_33_1","unstructured":"L.Schr\u00f6dingerandDeLano(2020) Retrieved fromhttp:\/\/www.pymol.org\/pymol."},{"key":"e_1_2_8_34_1","unstructured":"NeuroSnap AI accessed April 2026 Boltz\u20102 (AlphaFold3) Protein Structure Prediction Server. Available at: Boltz\u20102 (AlphaFold3) webserver:https:\/\/neurosnap.ai\/service\/Boltz\u20102%20(AlphaFold3)."},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci049885e"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.3567206","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.3567206","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.3567206","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:58:45Z","timestamp":1788785925000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.3567206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,7]]},"references-count":34,"alternative-id":["10.1002\/anie.3567206"],"URL":"https:\/\/doi.org\/10.1002\/anie.3567206","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,7]]},"assertion":[{"value":"2026-01-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e3567206"}}