Effects of BMS-986094, a guanosine nucleotide analogue, on mitochondrial DNA synthesis and function

Bethany R. Baumgart, Faye Wang, Jae Kwagh, Chris Storck, Catherine Euler, Megan Fuller, Damir Simic, Suresh D. Sharma, Jamie Jon Arnold, Craig Eugene Cameron, Terry R. Van Vleet, Oliver Flint, Roderick T. Bunch, Marc H. Davies, Michael J. Graziano, Thomas P. Sanderson

Research output: Contribution to journalArticle

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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BMS-986094, the prodrug of a guanosine nucleotide analogue (2'-C-methylguanosine), was withdrawn from clinical trials due to serious safety issues.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.

Original languageEnglish (US)
Pages (from-to)396-408
Number of pages13
JournalToxicological Sciences
Volume153
Issue number2
DOIs
StatePublished - Oct 1 2016

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Guanosine
Mitochondrial DNA
Nucleotides
Toxicity
Kidney
Macaca fascicularis
Prodrugs
Hep G2 Cells
DNA-Directed DNA Polymerase
DNA-Directed RNA Polymerases
Guanosine Triphosphate
Cardiac Myocytes
Gene expression
Haplorhini
INX 08189
Hepatocellular Carcinoma
Respiration
Adenosine Triphosphate
Clinical Trials
Safety

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Baumgart, B. R., Wang, F., Kwagh, J., Storck, C., Euler, C., Fuller, M., ... Sanderson, T. P. (2016). Effects of BMS-986094, a guanosine nucleotide analogue, on mitochondrial DNA synthesis and function. Toxicological Sciences, 153(2), 396-408. https://doi.org/10.1093/toxsci/kfw135
Baumgart, Bethany R. ; Wang, Faye ; Kwagh, Jae ; Storck, Chris ; Euler, Catherine ; Fuller, Megan ; Simic, Damir ; Sharma, Suresh D. ; Arnold, Jamie Jon ; Cameron, Craig Eugene ; Van Vleet, Terry R. ; Flint, Oliver ; Bunch, Roderick T. ; Davies, Marc H. ; Graziano, Michael J. ; Sanderson, Thomas P. / Effects of BMS-986094, a guanosine nucleotide analogue, on mitochondrial DNA synthesis and function. In: Toxicological Sciences. 2016 ; Vol. 153, No. 2. pp. 396-408.
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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.",
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Baumgart, BR, Wang, F, Kwagh, J, Storck, C, Euler, C, Fuller, M, Simic, D, Sharma, SD, Arnold, JJ, Cameron, CE, Van Vleet, TR, Flint, O, Bunch, RT, Davies, MH, Graziano, MJ & Sanderson, TP 2016, 'Effects of BMS-986094, a guanosine nucleotide analogue, on mitochondrial DNA synthesis and function', Toxicological Sciences, vol. 153, no. 2, pp. 396-408. https://doi.org/10.1093/toxsci/kfw135

Effects of BMS-986094, a guanosine nucleotide analogue, on mitochondrial DNA synthesis and function. / Baumgart, Bethany R.; Wang, Faye; Kwagh, Jae; Storck, Chris; Euler, Catherine; Fuller, Megan; Simic, Damir; Sharma, Suresh D.; Arnold, Jamie Jon; Cameron, Craig Eugene; Van Vleet, Terry R.; Flint, Oliver; Bunch, Roderick T.; Davies, Marc H.; Graziano, Michael J.; Sanderson, Thomas P.

In: Toxicological Sciences, Vol. 153, No. 2, 01.10.2016, p. 396-408.

Research output: Contribution to journalArticle

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T1 - Effects of BMS-986094, a guanosine nucleotide analogue, on mitochondrial DNA synthesis and function

AU - Baumgart, Bethany R.

AU - Wang, Faye

AU - Kwagh, Jae

AU - Storck, Chris

AU - Euler, Catherine

AU - Fuller, Megan

AU - Simic, Damir

AU - Sharma, Suresh D.

AU - Arnold, Jamie Jon

AU - Cameron, Craig Eugene

AU - Van Vleet, Terry R.

AU - Flint, Oliver

AU - Bunch, Roderick T.

AU - Davies, Marc H.

AU - Graziano, Michael J.

AU - Sanderson, Thomas P.

PY - 2016/10/1

Y1 - 2016/10/1

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