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Brown Research Fund for Blood Cancers"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    MDM2 is an E3 ubiquitin ligase that promotes p53 tumor suppressor degradation and has emerged as a therapeutic target in the treatment of wild-type (wt) TP53 tumors. In acute myeloid leukemia (AML), TP53 mutations are infrequent (15\u201320%), but wt-p53 is often inactivated through overexpression of MDM2. Thus, MDM2 inhibitors are currently in clinical trials for AML. However, p53 stabilization with inhibitors upregulates MDM2, which limits their clinical efficacy. Proteolysis-targeting chimeric (PROTAC) molecules that degrade MDM2 may overcome this feedback. MD-265 is a PROTAC that recruits CRBN, degrades MDM2, restores p53 and induces apoptosis. We tested MD-265 in ex vivo cultures of 105 primary leukemic stem cells (LSCs). The median cytotoxic IC\n                    <jats:sub>50<\/jats:sub>\n                    for MD-265 was 16\u2009nM, median IC\n                    <jats:sub>50<\/jats:sub>\n                    for MI-1061 was 150-fold higher. LSCs with IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009&gt;\u20091\u2009\u00b5M were classified as MD-265 resistant and harbored mutations in TP53. Normal hematopoietic stem cells showed 100-fold higher IC\n                    <jats:sub>50<\/jats:sub>\n                    (818\u2009nM) than LSCs. AML patient-derived xenograft (PDX) models in NSG-SGM3 mice were treated with MD-265 or an oral MDM2 inhibitor. In PDX models, MD-265 was not toxic and prolonged survival. MD-265 is a potent and specific MDM2 degrader with broad pre-clinical activity and a promising drug candidate for the treatment of leukemias.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-02957-8","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T07:53:23Z","timestamp":1776239603000},"page":"918-924","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models"],"prefix":"10.1038","volume":"40","author":[{"given":"Malathi","family":"Kandarpa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke F.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harish","family":"Potu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megha","family":"Ramappan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avery","family":"Polk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8782-6950","authenticated-orcid":false,"given":"Shaomeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3361-3981","authenticated-orcid":false,"given":"Moshe","family":"Talpaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"2957_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00425-3","volume":"11","author":"H Kantarjian","year":"2021","unstructured":"Kantarjian H, Kadia T, DiNardo C, Daver N, Borthakur G, Jabbour E, et al. 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S Wang is a co-inventor on one or more of these patent applications. S Wang was a co-founder of Ascentage, owns equity in Ascentage and is a paid consultant to Ascentage. The University of Michigan has also received a research contract from Ascentage.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}