TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Mitchell, Shaneice R.
A1  - Larkin, Karilyn
A1  - Grieselhuber, Nicole R.
A1  - Lai, Tzung-Huei
A1  - Cannon, Matthew
A1  - Orwick, Shelley
A1  - Sharma, Pratibha
A1  - Asemelash, Yerdanose
A1  - Zhang, Pu
A1  - Goettl, Virginia M.
A1  - Beaver, Larry
A1  - Mims, Alice
A1  - Puduvalli, Vinay K.
A1  - Blachly, James S.
A1  - Lehman, Amy
A1  - Harrington, Bonnie
A1  - Henderson, Sally
A1  - Breitbach, Justin T.
A1  - Williams, Katie E.
A1  - Dong, Shuai
A1  - Baloglu, Erkan
A1  - Senapedis, William
A1  - Kirschner, Karl
A1  - Sampath, Deepa
A1  - Lapalombella, Rosa
A1  - Byrd, John C.
T1  - Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia
JF  - Blood Advances
N2  - 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.
SN  - 2473-9529
SS  - 2473-9529
U6  - https://doi.org/10.1182/bloodadvances.2018024182
DO  - https://doi.org/10.1182/bloodadvances.2018024182
PM  - 30692102
N1  - 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.
VL  - 3
IS  - 3
SP  - 242
EP  - 255
PB  - American Society of Hematology
ER  -