{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T13:56:19Z","timestamp":1776952579907,"version":"3.51.4"},"reference-count":35,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22275037"],"award-info":[{"award-number":["22275037"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22520713700"],"award-info":[{"award-number":["22520713700"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["20ZR1404800"],"award-info":[{"award-number":["20ZR1404800"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"International Science &amp; Technology Innovation Collaboration Project of Shanghai","award":["22275037"],"award-info":[{"award-number":["22275037"]}]},{"name":"International Science &amp; Technology Innovation Collaboration Project of Shanghai","award":["22520713700"],"award-info":[{"award-number":["22520713700"]}]},{"name":"International Science &amp; Technology Innovation Collaboration Project of Shanghai","award":["20ZR1404800"],"award-info":[{"award-number":["20ZR1404800"]}]},{"name":"the Commission for Science and Technology of Shanghai","award":["22275037"],"award-info":[{"award-number":["22275037"]}]},{"name":"the Commission for Science and Technology of Shanghai","award":["22520713700"],"award-info":[{"award-number":["22520713700"]}]},{"name":"the Commission for Science and Technology of Shanghai","award":["20ZR1404800"],"award-info":[{"award-number":["20ZR1404800"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>N-(2-chloro-5-(3-(pyridin-4-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide, namely, FD274, is a promising 7-azaindazole-based PI3K inhibitor candidate with high antitumor efficacy against acute myeloid leukemia and reduced cardiotoxicity in the zebrafish model. To advance its clinical translation, in this work, we conducted comprehensive assessments of the cardiotoxicity of FD274 and preliminarily investigated its synergistic antitumor effects with an FLT3 inhibitor, Gilteritinib. The cardiotoxicity profile of FD274, as well as its bioisostere FD268 (positive control), was evaluated using the C57BL\/6 mouse model and the H9C2 cell line. The cardiotoxicity of FD274 after a consecutive 20-day treatment period was further assessed in an HL-60 xenograft mouse model. The synergistic cytotoxicity of FD274 with Gilteritinib was evaluated in the HL-60 cell line and the FLT3-ITD cell line MV-4-11. FD274 demonstrated lower adverse effects associated with cardiac dysfunction, oxidative stress, and myocardial injury in the C57BL\/6 mouse model and in the H9C2 cell line as compared with FD268. Its negligible adverse effect was further validated in the HL-60 xenograft mice after the 20-day treatment process. Moreover, FD274 demonstrated a synergistic pro-apoptotic effect with Gilteritinib in both HL-60 and MV-4-11 cells. Our findings confirmed the low cardiotoxicity of FD274 and its great potential for combination therapy with Gilteritinib, warranting further development.<\/jats:p>","DOI":"10.3390\/molecules30112347","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T03:52:08Z","timestamp":1748404328000},"page":"2347","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A PI3K Inhibitor with Low Cardiotoxicity and Its Synergistic Inhibitory Effect with Gilteritinib in Acute Myelogenous Leukemia (AML) Cells"],"prefix":"10.3390","volume":"30","author":[{"given":"Tianze","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Chemistry, Fudan University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yimin","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingzhu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengbin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yannan","family":"Yang","sequence":"additional","affiliation":[{"name":"South Australian immunoGENomics Cancer Institute, The University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6956-4504","authenticated-orcid":false,"given":"Yun","family":"Ling","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2720-9536","authenticated-orcid":false,"given":"Yaming","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1093\/toxsci\/kfp088","article-title":"Toxicity Testing in the 21st Century: A View from the Pharmaceutical Industry","volume":"110","author":"MacDonald","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ziegler, R., H\u00e4usermann, F., Kirchner, S., and Polonchuk, L. (2021). Cardiac Safety of Kinase Inhibitors\u2014Improving Understanding and Prediction of Liabilities in Drug Discovery Using Human Stem Cell-Derived Models. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.639824"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.1042\/CS20200302","article-title":"Cardiovascular toxicity of PI3K\u03b1 inhibitors","volume":"134","author":"Sadasivan","year":"2020","journal-title":"Clin. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1146\/annurev-med-062913-051343","article-title":"The PI3K\/AKT Pathway as a Target for Cancer Treatment","volume":"67","author":"Mayer","year":"2016","journal-title":"Annu. Rev. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s40264-018-0778-4","article-title":"Safety and Tolerability of Phosphatidylinositol-3-Kinase (PI3K) Inhibitors in Oncology","volume":"42","author":"Curigliano","year":"2019","journal-title":"Drug Safety"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1124\/jpet.117.246157","article-title":"Inhibition of the \u03b1-Subunit of Phosphoinositide 3-Kinase in Heart Increases Late Sodium Current and Is Arrhythmogenic","volume":"365","author":"Yang","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"760","DOI":"10.7150\/ijbs.65258","article-title":"Underlying the Mechanisms of Doxorubicin-Induced Acute Cardiotoxicity: Oxidative Stress and Cell Death","volume":"18","author":"Kong","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bouitbir, J., Panajatovic, M.V., and Kraehenbuehl, S. (2022). Mitochondrial Toxicity Associated with Imatinib and Sorafenib in Isolated Rat Heart Fibers and the Cardiomyoblast H9c2 Cell Line. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23042282"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"795602","DOI":"10.1155\/2015\/795602","article-title":"Chemotherapy-Induced Cardiotoxicity: Overview of the Roles of Oxidative Stress","volume":"2015","author":"Angsutararux","year":"2015","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.vph.2012.02.012","article-title":"Targeting NADPH oxidases in vascular pharmacology","volume":"56","author":"Schramm","year":"2012","journal-title":"Vasc. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.biopha.2017.08.129","article-title":"Perillyl alcohol protects human renal tubular epithelial cells from hypoxia\/reoxygenation injury via inhibition of ROS, endoplasmic reticulum stress and activation of PI3K\/Akt\/eNOS pathway","volume":"95","author":"Xu","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1161\/CIRCRESAHA.120.317011","article-title":"Heterodimerization with 5-HT2BR Is Indispensable for \u03b22AR-Mediated Cardioprotection","volume":"128","author":"Song","year":"2021","journal-title":"Circ. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1213\/ANE.0000000000005692","article-title":"Apelin-13 Reverses Bupivacaine-Induced Cardiotoxicity via the Adenosine Monophosphate-Activated Protein Kinase Pathway","volume":"133","author":"Ye","year":"2021","journal-title":"Anesth. Analg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1038\/s41467-019-09186-x","article-title":"Network-based prediction of drug combinations","volume":"10","author":"Cheng","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.gpb.2022.01.004","article-title":"SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets","volume":"20","author":"Zheng","year":"2022","journal-title":"Genom. Proteom. Bioinf."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1182\/blood-2016-09-693648","article-title":"How I treat FLT3-mutated AML","volume":"129","author":"Pratz","year":"2017","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Darici, S., Zavatti, M., Braglia, L., Accordi, B., Serafin, V., Horne, G.A., Manzoli, L., Palumbo, C., Huang, X., and J\u00f8rgensen, H.G. (2021). Synergistic cytotoxicity of dual PI3K\/mTOR and FLT3 inhibition in FLT3-ITD AML cells. Adv. Biol. Regul., 82.","DOI":"10.1016\/j.jbior.2021.100830"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhao, J., Song, Y., and Liu, D. (2019). Gilteritinib: A novel FLT3 inhibitor for acute myeloid leukemia. Biomark. Res., 7.","DOI":"10.1186\/s40364-019-0170-2"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1056\/NEJMoa1902688","article-title":"Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML","volume":"381","author":"Perl","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1158\/2159-8290.CD-18-1453","article-title":"Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia","volume":"9","author":"McMahon","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1021\/acsmedchemlett.7b00222","article-title":"Discovery of a Novel Series of 7-Azaindole Scaffold Derivatives as PI3K Inhibitors with Potent Activity","volume":"8","author":"Yang","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115543","DOI":"10.1016\/j.ejmech.2023.115543","article-title":"Discovery of N-(2-chloro-5-(3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (FD274) as a highly potent PI3K\/mTOR dual inhibitor for the treatment of acute myeloid leukemia","volume":"258","author":"Yang","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1007\/s12012-023-09809-2","article-title":"Systematical Evaluation of the Structure-Cardiotoxicity Relationship of 7-Azaindazole-based PI3K Inhibitors Designed by Bioisosteric Approach","volume":"23","author":"Wu","year":"2023","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1161\/CIRCRESAHA.115.303633","article-title":"Cardio-Oncology an Update on Cardiotoxicity of Cancer-Related Treatment","volume":"118","author":"Lenneman","year":"2016","journal-title":"Circ. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Morelli, M.B., Bongiovanni, C., Da Pra, S., Miano, C., Sacchi, F., Lauriola, M., and D\u2019Uva, G. (2022). Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.847012"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kitakata, H., Endo, J., Ikura, H., Moriyama, H., Shirakawa, K., Katsumata, Y., and Sano, M. (2022). Therapeutic Targets for DOX-Induced Cardiomyopathy: Role of Apoptosis vs. Ferroptosis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031414"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9287","DOI":"10.1158\/0008-5472.CAN-10-2664","article-title":"Nox2 NADPH Oxidase Promotes Pathologic Cardiac Remodeling Associated with Doxorubicin Chemotherapy","volume":"70","author":"Zhao","year":"2010","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.taap.2019.04.016","article-title":"Role of Nrf2 in the antioxidation and oxidative stress induced developmental toxicity of honokiol in zebrafish","volume":"373","author":"Li","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1512326","DOI":"10.1155\/2019\/1512326","article-title":"miR-200a Attenuated Doxorubicin-Induced Cardiotoxicity through Upregulation of Nrf2 in Mice","volume":"2019","author":"Hu","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"113661","DOI":"10.1016\/j.ejmech.2021.113661","article-title":"Bioisosteric replacements of the indole moiety for the development of a potent and selective PI3K\u03b4 inhibitor: Design, synthesis and biological evaluation","volume":"223","author":"Yang","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chen, Y., Wu, T.Z., Yang, C.B., Lu, M.Z., Chen, Z.X., Deng, M.L., Jia, Y., Yang, Y.T., Liu, X.F., and Wang, H.Y. (2022). A pyridinesulfonamide derivative FD268 suppresses cell proliferation and induces apoptosis via inhibiting PI3K pathway in acute myeloid leukemia. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0277893"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1161\/01.CIR.0000130647.29030.90","article-title":"Role of Akt signaling in mitochondrial survival pathway triggered by hypoxic preconditioning","volume":"109","author":"Uchiyama","year":"2004","journal-title":"Circulation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.scr.2013.01.002","article-title":"Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K\/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia\/reperfusion injury","volume":"10","author":"Arslan","year":"2013","journal-title":"Stem Cell Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.tips.2015.03.005","article-title":"Anthracyclines\/trastuzumab: New aspects of cardiotoxicity and molecular mechanisms","volume":"36","author":"Rochette","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Huang, A., Zeng, P., Li, Y., Lu, W., and Lai, Y. (2021). LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering with PI3K\/Akt Signaling Pathway. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.782065"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/11\/2347\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:41:48Z","timestamp":1760031708000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/11\/2347"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,27]]},"references-count":35,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["molecules30112347"],"URL":"https:\/\/doi.org\/10.3390\/molecules30112347","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,27]]}}}