title: Effects of BMS-986094, a Guanosine Nucleotide Analogue, on Mitochondrial DNA Synthesis and Function.
abstract: BMS-986094, the prodrug of a guanosine nucleotide analogue (2'-C-methylguanosine), was withdrawn from clinical trials due to serious safety issues. Nonclinical investigative studies were conducted as a follow up to evaluate the potential for BMS-986094-related mitochondrial-toxicity. In vitro, BMS-986094 was applied to human hepatoma cells (HepG2 and Huh-7) or cardiomyocytes (hiPSCM) up to 19 days to assess mitochondrial DNA content and specific gene expression. There were no mitochondrial DNA changes at concentrations ≤10 µM. Transcriptional effects, such as reductions in Huh-7 MT-ND1 and MT-ND5 mRNA content and hiPSCM MT-ND1, MT-COXII, and POLRMT protein expression levels, occurred only at cytotoxic concentrations (≥10 µM) suggesting these transcriptional effects were a consequence of the observed toxicity. Additionally, BMS-986094 has a selective weak affinity for inhibition of RNA polymerases as opposed to DNA polymerases. In vivo, BMS-986094 was given orally to cynomolgus monkeys for 3 weeks or 1 month at doses of 15 or 30 mg/kg/day. Samples of heart and kidney were collected for assessment of mitochondrial respiration, mitochondrial DNA content, and levels of high energy substrates. Although pronounced cardiac and renal toxicities were observed in some monkeys at 30 mg/kg/day treated for 3-4 weeks, there were no changes in mitochondrial DNA content or ATP/GTP levels. Collectively, these data suggest that BMS-986094 is not a direct mitochondrial toxicant.
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536 bethany.baumgart@bms.com.
authors.forename: Bethany R
authors.initials: BR
authors.lastname: Baumgart
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536.
authors.forename: Faye
authors.initials: F
authors.lastname: Wang
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536.
authors.forename: Jae
authors.initials: J
authors.lastname: Kwagh
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536.
authors.forename: Chris
authors.initials: C
authors.lastname: Storck
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536.
authors.forename: Catherine
authors.initials: C
authors.lastname: Euler
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536.
authors.forename: Megan
authors.initials: M
authors.lastname: Fuller
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536.
authors.forename: Damir
authors.initials: D
authors.lastname: Simic
authors.affiliation: The Pennsylvania State University, 201 Althouse Laboratory, University Park, Pennsylvania 16802.
authors.forename: Suresh
authors.initials: S
authors.lastname: Sharma
authors.affiliation: The Pennsylvania State University, 201 Althouse Laboratory, University Park, Pennsylvania 16802.
authors.forename: Jamie J
authors.initials: JJ
authors.lastname: Arnold
authors.affiliation: The Pennsylvania State University, 201 Althouse Laboratory, University Park, Pennsylvania 16802.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Cameron
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536.
authors.forename: Terry R
authors.initials: TR
authors.lastname: Van Vleet
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536.
authors.forename: Oliver
authors.initials: O
authors.lastname: Flint
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bunch
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536.
authors.forename: Marc H
authors.initials: MH
authors.lastname: Davies
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Graziano
authors.affiliation: *Bristol-Myers Squibb, 777 Scudders Mill Road, Princeton, New Jersey 08536.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sanderson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D006160:Guanosine Triphosphate / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006334:Heart Function Tests; D006801:Humans; D007291:Inosine Monophosphate / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007677:Kidney Function Tests; D008252:Macaca fascicularis; D008297:Male
chemical_list: D004272:DNA, Mitochondrial; D007291:Inosine Monophosphate; C553340:BMS-986094; D006157:Guanosine Monophosphate; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate
keywords: mitochondria; nucleotide analogue; toxicity