title: Cardiotoxicity Associated with Nicotinamide Phosphoribosyltransferase Inhibitors in Rodents and in Rat and Human-Derived Cells Lines.
abstract: Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein that functions as an enzyme, cytokine, growth factor and hormone. As a target for oncology, NAMPT is particularly attractive, because it catalyzes the rate-limiting step in the salvage pathway to generate nicotinamide adenine dinucleotide (NAD), a universal energy- and signal-carrying molecule involved in cellular energy metabolism and many homeostatic functions. Inhibition of NAMPT generally results in NAD depletion, followed by ATP reduction and loss of cell viability. Herein, we describe NAMPT inhibitor (NAMPTi)-induced cardiac toxicity in rodents following short-term administration (2-7 days) of NAMPTi's. The cardiac toxicity was interpreted as a functional effect leading to congestive heart failure, characterized by sudden death, thoracic and abdominal effusion, and myocardial degeneration. Based on exposures in the initial in vivo safety rodent studies and cardiotoxicity observed, we conducted studies in rat and human in vitro cardiomyocyte cell systems. Based on those results, combined with human cell line potency data, we demonstrated the toxicity is both on-target and likely human relevant. This toxicity was mitigated in vitro by co-administration of nicotinic acid (NA), which can enable NAD production through the NAMPT-independent pathway; however, this resulted in only partial mitigation in in vivo studies. This work also highlights the usefulness and predictivity of in vitro cardiomyocyte assays using human cells to rank-order compounds against potency in cell-based pharmacology assays. Lastly, this work strengthens the correlation between cardiomyocyte cell viability and functionality, suggesting that these assays together may enable early assessment of cardiotoxicity in vitro prior to conduct of in vivo studies and potentially reduce subsequent attrition due to cardiotoxicity.
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA. dinah.misner@gmail.com.
authors: D L
authors: 0000-0001-5054-678X
authors: DL
authors: Misner
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA.
authors: M A
authors: MA
authors: Kauss
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA.
authors: J
authors: J
authors: Singh
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA.
authors: H
authors: H
authors: Uppal
authors: ChanTest, 14656 Neo Parkway, Cleveland, OH, 44128, USA.
authors: A
authors: A
authors: Bruening-Wright
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA.
authors: B M
authors: BM
authors: Liederer
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA.
authors: T
authors: T
authors: Lin
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA.
authors: B
authors: B
authors: McCray
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA.
authors: N
authors: N
authors: La
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA.
authors: T
authors: T
authors: Nguyen
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA.
authors: D
authors: D
authors: Sampath
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA.
authors: P S
authors: PS
authors: Dragovich
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA.
authors: T
authors: T
authors: O'Brien
authors: Genentech, 1 DNA Way, M/S 59, South San Francisco, CA, 94080, USA.
authors: T S
authors: TS
authors: Zabka
mesh_terms: D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000633:toxicity; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000201:enzymology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013450:Sulfones / Q000633:toxicity
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; C000591022:GNE-617; D006574:Heterocyclic Compounds, 2-Ring; D013450:Sulfones; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: Cardiomyocytes; Cardiotoxicity; Heart; Impedance; Myocardial degeneration; Nicotinamide adenine dinucleotide; Nicotinic acid mononucleotide; Pathology; Tumor metabolism; Viability