{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T13:40:08Z","timestamp":1762522808523,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T00:00:00Z","timestamp":1671580800000},"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","award":["P30CA016058","R35CA198183","F30CA265281","F31CA254151"],"award-info":[{"award-number":["P30CA016058","R35CA198183","F30CA265281","F31CA254151"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"OSU Comprehensive Cancer Center Pelotonia foundation (SDB)","award":["P30CA016058","R35CA198183","F30CA265281","F31CA254151"],"award-info":[{"award-number":["P30CA016058","R35CA198183","F30CA265281","F31CA254151"]}]},{"name":"Pelotonia Fellowship Program (EDE)","award":["P30CA016058","R35CA198183","F30CA265281","F31CA254151"],"award-info":[{"award-number":["P30CA016058","R35CA198183","F30CA265281","F31CA254151"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Acute myeloid leukemia (AML) with mutations in the tumor suppressor gene TP53 confers a dismal prognosis with 3-year overall survival of &lt;5%. While inhibition of kinases involved in cell cycle regulation induces synthetic lethality in a variety of TP53 mutant cancers, this strategy has not been evaluated in mutant TP53 AML. Previously, we demonstrated that TP-0903 is a novel multikinase inhibitor with low nM activity against AURKA\/B, Chk1\/2, and other cell cycle regulators. Here, we evaluated the preclinical activity of TP-0903 in TP53 mutant AML cell lines, including a single-cell clone of MV4-11 containing a TP53 mutation (R248W), Kasumi-1 (R248Q), and HL-60 (TP 53 null). TP-0903 inhibited cell viability (IC50, 12\u201332 nM) and induced apoptosis at 50 nM. By immunoblot, 50 nM TP-0903 upregulated pChk1\/2 and pH2AX, suggesting induction of DNA damage. The combination of TP-0903 and decitabine was additive in vitro, and in vivo significantly prolonged median survival compared to single-agent treatments in mice xenografted with HL-60 (vehicle, 46 days; decitabine, 55 days; TP-0903, 63 days; combination, 75 days) or MV4-11 (R248W) (51 days; 62 days; 81 days; 89 days) (p &lt; 0.001). Together, these results provide scientific premise for the clinical evaluation of TP-0903 in combination with decitabine in TP53 mutant AML.<\/jats:p>","DOI":"10.3390\/cancers15010029","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T04:28:55Z","timestamp":1671596935000},"page":"29","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["TP-0903 Is Active in Preclinical Models of Acute Myeloid Leukemia with TP53 Mutation\/Deletion"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1176-675X","authenticated-orcid":false,"given":"Eric D.","family":"Eisenmann","sequence":"first","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8864-4617","authenticated-orcid":false,"given":"Jack C.","family":"Stromatt","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sydney","family":"Fobare","sequence":"additional","affiliation":[{"name":"Division of Hematology, The Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin M.","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daelynn R.","family":"Buelow","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4537-1409","authenticated-orcid":false,"given":"Shelley","family":"Orwick","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae Yoon","family":"Jeon","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert H.","family":"Weber","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bill","family":"Larsen","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice S.","family":"Mims","sequence":"additional","affiliation":[{"name":"Division of Hematology, The Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin","family":"Hertlein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John C.","family":"Byrd","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3062-3252","authenticated-orcid":false,"given":"Sharyn D.","family":"Baker","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41408-021-00425-3","article-title":"Acute Myeloid Leukemia: Current Progress and Future Directions","volume":"11","author":"Kantarjian","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e331","DOI":"10.1038\/bcj.2015.59","article-title":"TP53 Mutations in de Novo Acute Myeloid Leukemia Patients: Longitudinal Follow-Ups Show the Mutation Is Stable during Disease Evolution","volume":"5","author":"Hou","year":"2015","journal-title":"Blood Cancer J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13045-015-0139-z","article-title":"TP53 Mutation Characteristics in Therapy-Related Myelodysplastic Syndromes and Acute Myeloid Leukemia Is Similar to de Novo Diseases","volume":"8","author":"Ok","year":"2015","journal-title":"J. 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