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

• Main Authors: 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. McArthur, Ricky W. Johnstone
• Format: Article
• Language: English
• Published: Elsevier 2014-05-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124714002952

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.