@article{MitchellLarkinGrieselhuberetal.2019,
  author    = {Shaneice R. Mitchell and Karilyn Larkin and Nicole R. Grieselhuber and Tzung-Huei Lai and Matthew Cannon and Shelley Orwick and Pratibha Sharma and Yerdanose Asemelash and Pu Zhang and Virginia M. Goettl and Larry Beaver and Alice Mims and Vinay K. Puduvalli and James S. Blachly and Amy Lehman and Bonnie Harrington and Sally Henderson and Justin T. Breitbach and Katie E. Williams and Shuai Dong and Erkan Baloglu and William Senapedis and Karl Kirschner and Deepa Sampath and Rosa Lapalombella and John C. Byrd},
  title     = {Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia},
  series   = {Blood Advances},
  volume    = {3},
  number    = {3},
  publisher = {American Society of Hematology},
  issn      = {2473-9529},
  doi       = {10.1182/bloodadvances.2018024182},
  pages     = {242 -- 255},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}