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

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

SUBMITTER: Mitchell SR 

PROVIDER: S-EPMC6373756 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature