{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T07:12:10Z","timestamp":1790061130868,"version":"4.0.1"},"reference-count":8,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T00:00:00Z","timestamp":1624924800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T00:00:00Z","timestamp":1624924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01 CA223165"],"award-info":[{"award-number":["R01 CA223165"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R35 CA197734"],"award-info":[{"award-number":["R35 CA197734"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Hematol Oncol"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    KPT-9274 is a phase 1 first-in-class dual PAK4\/NAMPT inhibitor for solid tumor and non-Hodgkin\u2019s lymphoma. It demonstrates pre-clinical efficacy toward a broad spectrum of acute myeloid leukemia (AML) subtypes by inhibiting NAMPT-dependent NAD\n                    <jats:sup>+<\/jats:sup>\n                    production. NAMPT is the rate-limiting enzyme in the salvage metabolic pathway leading to NAD\n                    <jats:sup>+<\/jats:sup>\n                    generation. Tumor cells which are deficient in de novo pathway enzyme NAPRT1 are addicted to NAMPT. In clinical trials, treatment with NAMPT inhibitors resulted in dose-limiting toxicities. In order to dissect the mechanism of toxicity, mice were treated with KPT-9274 and resulting toxicities were characterized histopathologically and biochemically. KPT-9274 treatment caused gender-dependent stomach and kidney injuries and anemia. Female mice treated with KPT-9274 had EPO deficiency and associated impaired erythropoiesis. KPT-9274 treatment suppressed SIRT3 expression and concomitantly upregulated acetyl-manganese superoxide dismutase (MnSOD) in IMCD3 cells, providing a mechanistic basis for observed kidney toxicity. Importantly, niacin supplementation mitigated KPT-9274-caused kidney injury and EPO deficiency without affecting its efficacy. Altogether, our study delineated the mechanism of KPT-9274-mediated toxicity and sheds light onto developing strategies to improve the tolerability of this important anti-AML inhibitor.\n                  <\/jats:p>","DOI":"10.1186\/s13045-021-01107-0","type":"journal-article","created":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T08:02:42Z","timestamp":1624953762000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation"],"prefix":"10.1186","volume":"14","author":[{"given":"Shaneice","family":"Mitchell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Cannon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry","family":"Beaver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Lehman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonnie","family":"Harrington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa","family":"Sampath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Byrd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Lapalombella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,29]]},"reference":[{"issue":"1","key":"1107_CR1","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s10637-007-9083-2","volume":"26","author":"K Holen","year":"2008","unstructured":"Holen K, Saltz LB, Hollywood E, Burk K, Hanauske A-R. The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Investig New Drugs. 2008;26(1):45\u201351.","journal-title":"Investig New Drugs"},{"issue":"6","key":"1107_CR2","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1007\/s00280-009-1125-3","volume":"65","author":"A von Heideman","year":"2010","unstructured":"von Heideman A, Berglund A, Larsson R, Nygren P. Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data. Cancer Chemother Pharmacol. 2010;65(6):1165\u201372.","journal-title":"Cancer Chemother Pharmacol"},{"key":"1107_CR3","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.pharmthera.2015.02.004","volume":"151","author":"D Sampath","year":"2015","unstructured":"Sampath D, Zabka TS, Misner DL, O\u2019Brien T, Dragovich PS. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer. Pharmacol Ther. 2015;151:16\u201331.","journal-title":"Pharmacol Ther"},{"key":"1107_CR4","doi-asserted-by":"crossref","unstructured":"Naing A, Leong S, Pishvaian M, Razak A, Mahipal A, Berlin J, et al. A First in human phase 1 STUDY of KPT-9274, a first in class dual inhibitor of PAK4 and NAMPT, in patients with advanced solid malignancies or NHL. Ann Oncol. 2017;28.","DOI":"10.1093\/annonc\/mdx367.008"},{"issue":"3","key":"1107_CR5","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1182\/bloodadvances.2018024182","volume":"3","author":"SR Mitchell","year":"2019","unstructured":"Mitchell SR, Larkin K, Grieselhuber NR, Lai TH, Cannon M, Orwick S, et al. Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia. Blood Adv. 2019;3(3):242\u201355.","journal-title":"Blood Adv"},{"issue":"9","key":"1107_CR6","doi-asserted-by":"publisher","first-page":"2119","DOI":"10.1158\/1535-7163.MCT-16-0197","volume":"15","author":"O Abu Aboud","year":"2016","unstructured":"Abu Aboud O, Chen CH, Senapedis W, Baloglu E, Argueta C, Weiss RH. Dual and specific inhibition of NAMPT and PAK4 By KPT-9274 decreases kidney cancer growth. Mol Cancer Ther. 2016;15(9):2119\u201329.","journal-title":"Mol Cancer Ther"},{"key":"1107_CR7","doi-asserted-by":"crossref","unstructured":"London C, Brown M, Warry E, Schuh E, Senapedis WT, Argueta C, et al. Abstract LB-308: KPT-9274 inhibits cellular NAD and synergizes with doxorubicin to treat dogs with lymphoma. Cancer Res. 2017;77(13 Supplement):LB-308.","DOI":"10.1158\/1538-7445.AM2017-LB-308"},{"issue":"24","key":"1107_CR8","doi-asserted-by":"publisher","first-page":"6912","DOI":"10.1158\/1078-0432.CCR-13-1186","volume":"19","author":"DS Shames","year":"2013","unstructured":"Shames DS, Elkins K, Walter K, Holcomb T, Du P, Mohl D, et al. Loss of NAPRT1 expression by tumor-specific promoter methylation provides a novel predictive biomarker for NAMPT inhibitors. Clin Cancer Res. 2013;19(24):6912\u201323.","journal-title":"Clin Cancer Res"}],"container-title":["Journal of Hematology &amp; Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13045-021-01107-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13045-021-01107-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13045-021-01107-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T08:13:06Z","timestamp":1624954386000},"score":1,"resource":{"primary":{"URL":"https:\/\/jhoonline.biomedcentral.com\/articles\/10.1186\/s13045-021-01107-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,29]]},"references-count":8,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1107"],"URL":"https:\/\/doi.org\/10.1186\/s13045-021-01107-0","relation":{},"ISSN":["1756-8722"],"issn-type":[{"value":"1756-8722","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,29]]},"assertion":[{"value":"30 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"101"}}