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Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

  • Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.

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Document Type:Article
Author:Shaneice R. Mitchell, Karilyn Larkin, Nicole R. Grieselhuber, Tzung-Huei Lai, Matthew Cannon, Shelley Orwick, Pratibha Sharma, Yerdanose Asemelash, Pu Zhang, Virginia M. Goettl, Larry Beaver, Alice Mims, Vinay K. Puduvalli, James S. Blachly, Amy Lehman, Bonnie Harrington, Sally Henderson, Justin T. Breitbach, Katie E. Williams, Shuai Dong, Erkan Baloglu, William Senapedis, Karl Kirschner, Deepa Sampath, Rosa Lapalombella, John C. Byrd
Parent Title (English):Blood Advances
First Page:242
Last Page:255
Publisher:American Society of Hematology
Date of first publication:2019/01/28
Presented in abstract form at the 57th annual meeting of the American Society of Hematology, Orlando, FL, 7 December 2015; and in part at the 60th annual meeting of the American Society of Hematology, San Diego, CA, 3 December 2018.
Departments, institutes and facilities:Fachbereich Informatik
Dewey Decimal Classification (DDC):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Entry in this database:2019/02/06