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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:p>Oxygen sensing signaling is mainly mediated by EGLN prolyl hydroxylases, which plays important roles in physiology and diseases. Among them, EGLN2 plays an oncogenic role in breast cancer. However, the development of isoform-selective EGLN2 inhibitors remains a major challenge. Here, we report the identification of A10P3C, a small-molecule inhibitor that exhibits high potency and exceptional selectivity toward EGLN2. Guided by conformational sampling, ensemble-docking-based functional-group-residue contact analysis and simulation-based binding selectivity design, A10P3C was designed and strategically improved from an initially screened lead compound to selectively inhibit EGLN2. Unlike previously reported pan-hydroxylase inhibitors, A10P3C achieves potent isoform selectivity. Functionally, A10P3C effectively suppresses breast cancer cell proliferation, migration, and invasion, while inducing G1 cell cycle arrest and cellular senescence through on-target EGLN2 inhibition. These on-target effects are corroborated by transcriptomic profiling, which shows significant modulation of cell cycle and senescence pathways. Notably, A10P3C exhibits robust antitumor efficacy in patient-derived organoids and xenograft models, accompanied by favorable metabolic stability and minimal systemic toxicity. Collectively, these findings identify A10P3C as a selective chemical probe for EGLN2 biology and a promising therapeutic lead for precision treatment of EGLN2-driven breast cancers.<\/jats:p>","DOI":"10.1073\/pnas.2613915123","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:09:36Z","timestamp":1790870976000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Development of A10P3C, an isoform-selective inhibitor of EGLN2, for targeting breast cancer"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7951-7381","authenticated-orcid":false,"given":"Qian","family":"Liang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05byvp690","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology, University of Texas Southwestern Medical 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