{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T18:27:52Z","timestamp":1787682472248,"version":"build-2784847793"},"reference-count":78,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T00:00:00Z","timestamp":1775260800000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The menin\u2013lysine methyltransferase 2A acute leukemia (KMT2A) protein\u2013protein interaction has emerged as a clinically validated epigenetic target in acute leukemia, following the approval of the reversible menin inhibitor Revumenib for\n                    <jats:italic>KMT2A<\/jats:italic>\n                    \u2010rearranged and nucleophosmin 1 (NPM1)\u2010mutant disease. This success transformed a once \u201cundruggable\u201d interface into a tractable binding pocket, triggering the rapid expansion of medicinal\u2010chemistry strategies aimed at achieving deeper and more durable transcriptional reprogramming. This review analyzes the full menin\u2010inhibitor landscape from a medicinal\u2010chemistry perspective, integrating reversible, covalent, and degrader\u2010oriented modalities within a unified structure\u2013activity framework. We highlight how scaffold architecture, pocket occupancy, electrophile placement toward Cys329, and polarity tuning control binding mode, residence time, metabolic stability, resistance susceptibility, and pharmacodynamic durability. Across all chemical classes, sustained target engagement\u2014rather than equilibrium affinity alone\u2014emerges as the dominant determinant of antileukemic efficacy. By integrating structure\u2013activity relationship (SAR), resistance mechanisms, safety considerations, and translational scope across oncology and metabolic indications, this review provides a roadmap for the rational design of next\u2010generation menin inhibitors and establishes menin as a model system for modern epigenetic drug discovery.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70291","type":"journal-article","created":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T20:59:33Z","timestamp":1775336373000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting the Menin\u2013\n                    <i>KMT2A<\/i>\n                    Interface: Medicinal Chemistry Rules Governing Reversible, Covalent, and Degrader Inhibitors"],"prefix":"10.1111","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8173-6073","authenticated-orcid":false,"given":"Ahmed A.","family":"Al\u2010Karmalawy","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Horus University\u2010Egypt  New Damietta Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed E.","family":"Eissa","sequence":"additional","affiliation":[{"name":"Chemistry Department, College of Science Imam Mohammad Ibn Saud Islamic University (IMSIU)  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3039-7646","authenticated-orcid":false,"given":"Tarek A.","family":"Yousef","sequence":"additional","affiliation":[{"name":"Chemistry Department, College of Science Imam Mohammad Ibn Saud Islamic University (IMSIU)  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7894-3514","authenticated-orcid":false,"given":"Marwa","family":"Sharaky","sequence":"additional","affiliation":[{"name":"Cancer Biology Department, Pharmacology Unit, National Cancer Institute (NCI) Cairo University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9445-3315","authenticated-orcid":false,"given":"Arwa Omar","family":"Al Khatib","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Al\u2010Ahliyya Amman University  Amman Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samia S.","family":"Hawas","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Horus University\u2010Egypt  New Damietta Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,4]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935\u2010022\u201002740\u20106"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01668"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2022.2124409"},{"key":"e_1_2_15_5_1","doi-asserted-by":"crossref","unstructured":"Apostolidou E. 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