{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:04:21Z","timestamp":1790730261190,"version":"4.1.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>FDA-approved BRAF and MEK small molecule inhibitors have demonstrated some level of efficacy in patients with metastatic melanomas. However, these \u201ctargeted\u201d therapeutics have a very low therapeutic index, since these agents affect normal cells, causing undesirable, even fatal, side effects. To address these significant drawbacks, here, we have reengineered the anthrax toxin-based protein delivery system to develop a potent, tumor-selective MEK inactivator. This toxin-based MEK inactivator exhibits potent activity against a wide range of solid tumors, with the highest activity seen when directed toward tumors containing the BRAFV600E mutation. We demonstrate that this reengineered MEK inactivator also exhibits an extremely high therapeutic index (&amp;gt;15), due to its in vitro and in vivo activity being strictly dependent on the expression of multiple tumor-associated factors including tumor-associated proteases matrix metalloproteinase, urokinase plasminogen activator, and anthrax toxin receptor capillary morphogenesis protein-2. Furthermore, we have improved the specificity of this MEK inactivator, restricting its enzymatic activity to only target the ERK pathway, thereby greatly diminishing off-target toxicity. Together, these data suggest that engineered bacterial toxins can be modified to have significant in vitro and in vivo therapeutic effects with high therapeutic index.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgac104","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T11:57:20Z","timestamp":1656676640000},"source":"Crossref","is-referenced-by-count":7,"title":["A potent tumor-selective ERK pathway inactivator with high therapeutic index"],"prefix":"10.1093","volume":"1","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6240-5394","authenticated-orcid":false,"given":"Zehua","family":"Zuo","sequence":"first","affiliation":[{"name":"Aging Institute of University of Pittsburgh and University of Pittsburgh Medical Center , Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1549-2012","authenticated-orcid":false,"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Aging Institute of University of Pittsburgh and University of Pittsburgh Medical Center , Pittsburgh, PA 15219, USA"},{"name":"Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihao","family":"Sun","sequence":"additional","affiliation":[{"name":"Aging Institute of University of Pittsburgh and University of Pittsburgh Medical Center , Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Silverstein","sequence":"additional","affiliation":[{"name":"Aging Institute of University of Pittsburgh and University of Pittsburgh Medical Center , Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijuan","family":"Zou","sequence":"additional","affiliation":[{"name":"Aging Institute of University of Pittsburgh and University of Pittsburgh Medical Center , Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toren","family":"Finkel","sequence":"additional","affiliation":[{"name":"Aging Institute of University of Pittsburgh and University of Pittsburgh Medical Center , Pittsburgh, PA 15219, USA"},{"name":"Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H","family":"Bugge","sequence":"additional","affiliation":[{"name":"Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health , Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5233-0501","authenticated-orcid":false,"given":"Stephen H","family":"Leppla","sequence":"additional","affiliation":[{"name":"Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3444-1069","authenticated-orcid":false,"given":"Shihui","family":"Liu","sequence":"additional","affiliation":[{"name":"Aging Institute of University of Pittsburgh and University of Pittsburgh Medical Center , Pittsburgh, PA 15219, USA"},{"name":"Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA 15219, 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