Journal article
The drug vehicle and solvent N-Methylpyrrolidone is an immunomodulator and antimyeloma compound
J Shortt, AK Hsu, BP Martin, K Doggett, GM Matthews, MA Doyle, J Ellul, TE Jockel, DM Andrews, SJ Hogg, A Reitsma, D Faulkner, PL Bergsagel, M Chesi, JK Heath, WA Denny, PE Thompson, PJ Neeson, DS Ritchie, GA McArthur Show all
Cell Reports | Published : 2014
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 ..
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Funding Acknowledgements
The authors thank Prof. James Bradner and Prof. Constantine Mitsiades for advice and critical evaluation of experimental data. Dr. Chris Ott and Dr. Gang Lu provided assistance with IKZF assays. J.S. is supported by the Leukaemia Foundation of Australia and the Co-operative Research Centre for Biomedical Imaging Development. T.E.J. is supported by Deutsche Krebshilfe. R.W.J. is a Principal Research Fellow of the National Health and Medical Research Council (NHMRC) of Australia and supported by NHMRC Program and Project Grants, Cancer Council Victoria, the Leukaemia Foundation of Australia, and the Victorian Cancer Agency.