{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:00:19Z","timestamp":1790600419776,"version":"4.1.0"},"reference-count":44,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Joint Funds for the innovation of science and Technology???Fujian province","award":["2024Y9406"],"award-info":[{"award-number":["2024Y9406"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Despite the broad success of targeted protein degradation (TPD), achieving efficient degradation within mitochondria remains a challenge. Herein, we report a highly active degrader targeting human mitochondrial RNA polymerase (POLRMT) based on the Mitochondrial Protease Targeting Chimeras (MtPTACs) strategy. The lead compound, MTP-B1, is a highly potent MtPTAC to achieve essentially complete target degradation (Dmax &amp;gt; 98%) within 24 h at sub-micromolar concentrations. Mechanistically, MTP-B1 circumvents the compensatory transcriptional upregulation induced by POLRMT inhibitors and sustains downstream signaling suppression in washout assays. Remarkably, under the dosing regimens tested, MTP-B1 exhibited greater in vivo antitumor efficacy than the co-administration of a POLRMT inhibitor and a ClpP activator, highlighting the therapeutic potential of targeted protein degradation in mitochondria. These findings, further supported by the extension to a second target, dihydroorotate dehydrogenase (DHODH), provide high-efficiency MtPTACs as a powerful and generalizable modality for mitochondrial medicine.<\/jats:p>","DOI":"10.1021\/jacsau.6c01255","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:02:04Z","timestamp":1788951724000},"page":"5439-5454","source":"Crossref","is-referenced-by-count":0,"title":["Development of High-Efficiency\nMitochondrial Protease\nTargeting Chimeras (MtPTACs) for Targeted Degradation of POLRMT and\nBeyond"],"prefix":"10.1021","volume":"6","author":[{"given":"Cong","family":"Chen","sequence":"first","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Liu","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinnan","family":"Li","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuning","family":"Shi","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieya","family":"Zhou","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijuan","family":"Huang","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyue","family":"Zeng","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dazhi","family":"Feng","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyue","family":"Wang","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyang","family":"Nie","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanyi","family":"Huang","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Wu","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaokang","family":"Pang","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1961-0402","authenticated-orcid":true,"given":"Jinyi","family":"Xu","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5705-6377","authenticated-orcid":true,"given":"Shengtao","family":"Xu","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9594-9598","authenticated-orcid":true,"given":"Hong","family":"Yao","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 639 Longmian Avenue , ,","place":["Nanjing, P. R. China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"2026092808090119400_cit1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41568-025-00817-8","article-title":"Targeted protein\ndegradation for cancer therapy","volume":"25","author":"Hinterndorfer","year":"2025","journal-title":"Nat. Rev. Cancer"},{"key":"2026092808090119400_cit2","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1038\/d41573-024-00170-9","article-title":"Protein degraders\npush into novel target space","volume":"23","author":"Mullard","year":"2024","journal-title":"Nat. Rev. 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Today"},{"key":"2026092808090119400_cit11","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40680-5","article-title":"Mitochondria\nare secreted in extracellular vesicles\nwhen lysosomal function is impaired","volume":"14","author":"Liang","year":"2023","journal-title":"Nat. Commun."},{"key":"2026092808090119400_cit12","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/s41580-020-00300-2","article-title":"Quality control\nof the mitochondrial\nproteome","volume":"22","author":"Song","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2026092808090119400_cit13","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-025-00505-5","article-title":"Molecular mechanisms of mitochondrial\nquality control","volume":"14","author":"Li","year":"2025","journal-title":"Transl. Neurodegener."},{"key":"2026092808090119400_cit14","doi-asserted-by":"publisher","DOI":"10.1186\/s40779-024-00536-5","article-title":"Mitochondrial quality\ncontrol in human health and disease","volume":"11","author":"Liu","year":"2024","journal-title":"Mil. Med.\nRes."},{"key":"2026092808090119400_cit15","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1002\/med.21929","article-title":"Mitochondrial\nquality control proteases\nand their modulation for cancer therapy","volume":"43","author":"Zhang","year":"2023","journal-title":"Med.\nRes. Rev."},{"key":"2026092808090119400_cit16","doi-asserted-by":"publisher","first-page":"12861","DOI":"10.1021\/jacs.3c03756","article-title":"Mitochondrial\nProtease Targeting Chimeras for Mitochondrial Matrix Protein Degradation","volume":"145","author":"Wang","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"2026092808090119400_cit17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpet.2025.103729","article-title":"Targeting mitochondrial RNA polymerase for triple-negative\nbreast cancer","volume":"392","author":"Lai","year":"2025","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2026092808090119400_cit18","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2025.118350","article-title":"ClpP-based MtPTAC technology\nenables targeted degradation of inner\nmitochondrial membrane proteins","volume":"130","author":"Yao","year":"2025","journal-title":"Bioorg. Med.\nChem."},{"key":"2026092808090119400_cit19","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-06203-2","article-title":"Identification\nof the mitochondrial protein POLRMT as a potential therapeutic target\nof prostate cancer","volume":"14","author":"Li","year":"2023","journal-title":"Cell Death Dis."},{"key":"2026092808090119400_cit20","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05682-7","article-title":"A first-in-class\nPOLRMT specific inhibitor IMT1 suppresses endometrial carcinoma cell\ngrowth","volume":"14","author":"Li","year":"2023","journal-title":"Cell Death Dis."},{"key":"2026092808090119400_cit21","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-06444-9","article-title":"Targeting POLRMT by\na first-in-class inhibitor IMT1 inhibits osteosarcoma\ncell growth in vitro and in vivo","volume":"15","author":"Kong","year":"2024","journal-title":"Cell Death\nDis."},{"key":"2026092808090119400_cit22","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines11061598","article-title":"Targeting\nMitochondrial\nDNA Transcription by POLRMT Inhibition or Depletion as a Potential\nStrategy for Cancer Treatment","volume":"11","author":"Daglish","year":"2023","journal-title":"Biomedicines"},{"key":"2026092808090119400_cit23","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1038\/s41586-020-03048-z","article-title":"Small-molecule inhibitors of human mitochondrial DNA\ntranscription","volume":"588","author":"Bonekamp","year":"2020","journal-title":"Nature"},{"key":"2026092808090119400_cit24","doi-asserted-by":"publisher","first-page":"15691","DOI":"10.1002\/cam4.6174","article-title":"POLRMT over-expression is linked\nto WNT\/beta-catenin signaling, immune\ninfiltration, and unfavorable outcomes in lung adenocarcinoma patients","volume":"12","author":"Huang","year":"2023","journal-title":"Cancer Med."},{"key":"2026092808090119400_cit25","doi-asserted-by":"publisher","first-page":"15495","DOI":"10.1021\/acs.jmedchem.5c00130","article-title":"Design, Optimization,\nand Biological Evaluation of a Novel Quinoline-Based POLRMT Inhibitor\nfor Prostate Cancer Therapy","volume":"68","author":"Li","year":"2025","journal-title":"J. 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Cancer Res."},{"key":"2026092808090119400_cit31","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1080\/15548627.2018.1474314","article-title":"Chloroquine inhibits autophagic flux by decreasing\nautophagosome-lysosome fusion","volume":"14","author":"Mauthe","year":"2018","journal-title":"Autophagy"},{"key":"2026092808090119400_cit32","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2024.123125","article-title":"Bortezomib in cancer\ntherapy: Mechanisms, side effects,\nand future proteasome inhibitors","volume":"358","author":"Sogbein","year":"2024","journal-title":"Life Sci."},{"key":"2026092808090119400_cit33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2422447122","article-title":"Serine\nphosphorylation facilitates protein degradation by the human mitochondrial\nClpXP protease","volume":"122","author":"Feng","year":"2025","journal-title":"Proc. Natl. Acad. Sci. 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Visualized Exp."},{"key":"2026092808090119400_cit40","doi-asserted-by":"publisher","first-page":"e1150","DOI":"10.1016\/j.clbc.2025.05.013","article-title":"Tumor ki67\nImpact on Survival in\nMale Breast Cancer Patients: A Systematic Review and Meta-Analysis","volume":"25","author":"Kinsey-Trotman","year":"2025","journal-title":"Clin. Breast Cancer"},{"key":"2026092808090119400_cit41","doi-asserted-by":"publisher","DOI":"10.1016\/j.crmeth.2025.101047","article-title":"Harmonizing TUNEL with multiplexed\niterative immunofluorescence\nenriches spatial contextualization of cell death","volume":"5","author":"Sherman","year":"2025","journal-title":"Cells Rep. 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