{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:02:05Z","timestamp":1789466525705,"version":"build-2803163510"},"reference-count":36,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2025,8,16]]},"abstract":"<jats:p>Dual inhibition of the negative p53 regulators MDM2 and MDMX has emerged as an effective strategy in p53\u2010based anticancer therapy. However, dual inhibitors are limited, and many inhibitors exhibit poor pharmacokinetic properties and fast dissociation kinetics. Among newly identified microbial metabolites, the novel phenylalanine\u2010derived compound P5 isolated from <jats:italic>Micromonospora<\/jats:italic> sp. MS\u201062 (FBCC\u2010B8445) exhibits inhibitory activity against both MDM2 and MDMX. The binding of P5 to MDM2 and MDMX is demonstrated by surface plasmon resonance, which reveals nanomolar\u2010level affinity and slow dissociation kinetics (KD\u2009=\u200946 nM for MDM2; 576 nM for MDMX). This dual inhibitory activity was further supported by molecular docking, which reveals binding of P5 to the p53\u2010binding pockets of both MDM2 and MDMX through extensive noncovalent interactions. In cell\u2010based assays, P5 reduced cancer cell viability across several human cell lines. Furthermore, <jats:italic>in silico<\/jats:italic> analysis indicates favorable pharmacokinetic properties, including gastrointestinal absorption, blood\u2013brain barrier permeability, and compliance with Lipinski's and Veber's criteria. P5 combines dual\u2010target engagement with binding persistence and favorable pharmacokinetic characteristics, addressing limitations of earlier inhibitors. P5 is a potential lead compound for the development of MDM2\/MDMX\u2010targeted anticancer agents.<\/jats:p>","DOI":"10.1002\/cmdc.202500397","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T10:48:17Z","timestamp":1751021297000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Discovery of a Phenylalanine\u2010Derived Natural Compound as a Potential Dual Inhibitor of MDM2 and MDMX"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4301-6961","authenticated-orcid":false,"given":"Ja Young","family":"Cho","sequence":"first","affiliation":[{"name":"Prokaryote Research Division Nakdonggang National Institute of Biological Resources (NNIBR)  Sangju 37242 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanghwa","family":"Park","sequence":"additional","affiliation":[{"name":"Bio\u2010resources Bank Division Nakdonggang National Institute of Biological Resources (NNIBR)  Sangju 37242 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taejung","family":"Kim","sequence":"additional","affiliation":[{"name":"Institute of Natural Products Korea Institute of Science and Technology (KIST)  Gangneung 25451 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junghye","family":"Eom","sequence":"additional","affiliation":[{"name":"Prokaryote Research Division Nakdonggang National Institute of Biological Resources (NNIBR)  Sangju 37242 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6443-632X","authenticated-orcid":false,"given":"Jung\u2010Rae","family":"Rho","sequence":"additional","affiliation":[{"name":"Department of Oceanography Kunsan National University  Gunsan 54150 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1122-171X","authenticated-orcid":false,"given":"Hyoung\u2010Woo","family":"Bai","sequence":"additional","affiliation":[{"name":"Research division for Biotechnology Advanced Radiation Technology Institute (ARTI) Korea Atomic Energy Research Institute (KAERI)  Jeongeup 56212 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/bbb\/zbae036"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13020-018-0192-y"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00572-w"},{"key":"e_1_2_8_5_1","first-page":"5762","volume":"11","author":"Munisamy M.","year":"2021","journal-title":"Am. J. Cancer Res."},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23095005"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-021-01406-x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2021.1924267"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aao3003"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2022.155445"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/md19020105"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25040853"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/md19020075"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jnatprod.9b01285"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-25682-4"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7033-9_21"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-2425-7_7"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0900947106"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00940"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-15-0467"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1015"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.compbiomed.2021.104851"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2015.12.047"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28721-x"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s44371-024-00071-1"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.9.6.11067"},{"key":"e_1_2_8_27_1","first-page":"25","volume":"1","author":"Mohanty M.","year":"2023","journal-title":"Monatsh. Chem."},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232415961"},{"key":"e_1_2_8_29_1","first-page":"3321","volume":"30","author":"Zheng M.","year":"2010","journal-title":"Anticancer Res."},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1203789109"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2102420118"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep42717"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201600182"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci500467k"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21256"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/1758-2946-3-33"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21334"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202500397","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T15:22:43Z","timestamp":1760282563000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202500397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,22]]},"references-count":36,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2025,8,16]]}},"alternative-id":["10.1002\/cmdc.202500397"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202500397","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,22]]},"assertion":[{"value":"2025-05-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202500397"}}