{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:11:34Z","timestamp":1790208694560,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"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":[],"crossmark-restriction":false},"short-container-title":["MedComm"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The positive transcription elongation factor b (P\u2010TEFb) complex, composed of CDK9 and cyclin T isoforms (T1, T2a and T2b), is critical for gene transcription, positioning CDK9 as a very promising oncology target. However, the development of selective and clinically effective small\u2010molecule CDK9 inhibitors has proven challenging. To overcome this limitation, we designed a series of highly efficient and selective P\u2010TEFb degraders by conjugating the CDK9 inhibitor SNS032 with the mouse double minute 2 (MDM2) ligand RG7388. Our lead compound,\n                    <jats:bold>13<\/jats:bold>\n                    (dCDK9\u2010010), recruits the MDM2 E3 ligase to induce proteasome\u2010dependent degradation of CDK9 and all cyclin T isoforms across diverse cancer models. dCDK9\u2010010 potently inhibits RNA polymerase II carboxy\u2010terminal repeat domain phosphorylation and blocks MDM2\u2010mediated p53 degradation, resulting in concurrent p53 pathway activation. This dual mechanism drives selective cytotoxicity in\n                    <jats:italic>TP53<\/jats:italic>\n                    wild\u2010type cancer cells, sparing\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010mutant or nonmalignant cells. In murine xenograft models of lung cancer and Ewing sarcoma, intravenous dCDK9\u2010010 administration significantly inhibited tumor growth while demonstrating an excellent safety profile. Collectively, this study establishes dCDK9\u2010010 as a first\u2010in\u2010class, selective MDM2\u2010recruiting P\u2010TEFb degrader. By enabling the elimination of the entire P\u2010TEFb complex, this MDM2\u2010recruiting degradation strategy expands the toolkit for targeting CDK9 and represents a promising new therapeutic paradigm for\n                    <jats:italic>TP53<\/jats:italic>\n                    wild\u2010type cancers.\n                  <\/jats:p>","DOI":"10.1002\/mco2.70723","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:48:29Z","timestamp":1775803709000},"source":"Crossref","is-referenced-by-count":2,"title":["Discovery of a First\u2010in\u2010Class Murine Double Minute 2\u2010Recruiting Positive Transcription Elongation Factor B PROTAC Degrader With Selective Antitumor Activity"],"prefix":"10.1002","volume":"7","author":[{"given":"Xian","family":"Guan","sequence":"first","affiliation":[{"name":"Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital and Institute of 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