The drug vehicle and solvent N-Methylpyrrolidone is an immunomodulator and antimyeloma compound

Jake Shortt, Andy K. Hsu, Benjamin P. Martin, Karen Doggett, Geoffrey M. Matthews, Maria A. Doyle, Jason Ellul, Tina E. Jockel, Daniel M. Andrews, Simon J. Hogg, Andrea Reitsma, David Faulkner, P. Leif Bergsagel, Marta Chesi, Joan K. Heath, William A. Denny, Philip E. Thompson, Paul J. Neeson, David S. Ritchie, Grant A. McArthurRicky W. Johnstone

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

N-methyl-2-pyrrolidone (NMP) is a common solvent and drug vehicle. We discovered unexpected antineoplastic and immunomodulatory activity of NMP in a cMYC-driven myeloma model. Coincident to this, NMP was identified as an acetyllysine mimetic and candidate bromodomain ligand. Accordingly, NMP-treated cells demonstrated transcriptional overlap with BET-bromodomain inhibition, including downregulation of cMYC and IRF4. NMP's immunomodulatory activity occurred at sub-BET inhibitory concentrations, and, despite phenotypic similarities to lenalidomide, its antimyeloma activity was independent of the IMiD targets cereblon and Ikaros-1/3. Thus, low-affinity yet broad-spectrum bromodomain inhibition by NMP mediates biologically potent, cereblon-independent immunomodulation and at higher doses targets malignant cells directly via BET antagonism. These data reveal that NMP is a functional acetyllysine mimetic with pleotropic antimyeloma and immunomodulatory activities. Our studies highlight the potential therapeutic benefits of NMP, the consequences of current human NMP exposures, and the need for reassessment of scientific literature where NMP was used as an "inert" drug-delivery vehicle.

Original languageEnglish (US)
Pages (from-to)1009-1019
Number of pages11
JournalCell reports
Volume7
Issue number4
DOIs
StatePublished - May 22 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Shortt, J., Hsu, A. K., Martin, B. P., Doggett, K., Matthews, G. M., Doyle, M. A., Ellul, J., Jockel, T. E., Andrews, D. M., Hogg, S. J., Reitsma, A., Faulkner, D., Bergsagel, P. L., Chesi, M., Heath, J. K., Denny, W. A., Thompson, P. E., Neeson, P. J., Ritchie, D. S., ... Johnstone, R. W. (2014). The drug vehicle and solvent N-Methylpyrrolidone is an immunomodulator and antimyeloma compound. Cell reports, 7(4), 1009-1019. https://doi.org/10.1016/j.celrep.2014.04.008