The Drug Vehicle and Solvent N-Methylpyrrolidone Is an Immunomodulator and Antimyeloma Compound

• Published in: Cell reports (Cambridge) Vol. 7; no. 4; pp. 1009 - 1019
• Main Authors: Shortt, Jake, Hsu, Andy K., Martin, Benjamin P., Doggett, Karen, Matthews, Geoffrey M., Doyle, Maria A., Ellul, Jason, Jockel, Tina E., Andrews, Daniel M., Hogg, Simon J., Reitsma, Andrea, Faulkner, David, Bergsagel, P. Leif, Chesi, Marta, Heath, Joan K., Denny, William A., Thompson, Philip E., Neeson, Paul J., Ritchie, David S., McArthur, Grant A., Johnstone, Ricky W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.05.2014; Elsevier
• Subjects: Animals; Antineoplastic Agents - pharmacology; Cell Differentiation - drug effects; Cells, Cultured; Humans; Immunologic Factors - pharmacology; Mice; Mice, Inbred C57BL; Multiple Myeloma - drug therapy; Multiple Myeloma - immunology; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Pyrrolidinones - pharmacology; Signal Transduction - drug effects; Xenograft Model Antitumor Assays
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.04.008

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. [Display omitted] •NMP functions as a nonselective acetyllysine mimetic and bromodomain ligand•NMP is a biologically potent, cereblon-independent immunomodulator•Bromodomain inhibitors and IMiDs have highly convergent gene expression signatures•Common NMP exposures occur at bromodomain-inhibitory concentrations N-methyl-2-pyrrolidone (NMP) is an industrial solvent and pharmacological delivery vehicle. Shortt et al. now find unexpected immunostimulatory, anti-inflammatory, and antimyeloma activity of NMP. Subsequent experiments reveal that NMP is an acetylated lysine mimetic and inhibitor of bromodomain-containing histone “reader” proteins. Low NMP concentrations exhibited immunomodulatory properties reminiscent of structurally unrelated thalidomide analogs. Higher NMP doses directly downregulated critical myeloma oncogenes, including cMYC and IRF4. The potential effect of exposure to NMP requires urgent reassessment.