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

Autor:	Mitchell SR; Division of Hematology., Larkin K; Division of Hematology., Grieselhuber NR; Division of Hematology., Lai TH; Division of Hematology., Cannon M; Division of Hematology., Orwick S; Division of Hematology., Sharma P; Division of Neuro-oncology., Asemelash Y; Division of Hematology., Zhang P; Division of Hematology., Goettl VM; Division of Hematology., Beaver L; Division of Hematology., Mims A; Division of Hematology., Puduvalli VK; Division of Neuro-oncology., Blachly JS; Division of Hematology., Lehman A; Center for Biostatistics, and., Harrington B; College of Veterinary Medicine, The Ohio State University, Columbus, OH., Henderson S; College of Veterinary Medicine, The Ohio State University, Columbus, OH., Breitbach JT; College of Veterinary Medicine, The Ohio State University, Columbus, OH., Williams KE; Division of Hematology., Dong S; Division of Hematology., Baloglu E; Karyopharm Therapeutics Inc., Newton, MA., Senapedis W; Karyopharm Therapeutics Inc., Newton, MA., Kirschner K; Departments of Computer Science and Electrical Engineering, Mechanical Engineering and Technical Journalism, Bonn-Rhein-Sieg University of Applied Sciences, Sankt Augustin, Germany; and., Sampath D; Division of Hematology., Lapalombella R; Division of Hematology., Byrd JC; Division of Hematology.; College of Veterinary Medicine, The Ohio State University, Columbus, OH.; Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2019 Feb 12; Vol. 3 (3), pp. 242-255.
DOI:	10.1182/bloodadvances.2018024182
Abstrakt:	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. (© 2019 by The American Society of Hematology.)
Databáze:	MEDLINE
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