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.

中文翻译：

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药物媒介物和溶剂N-甲基吡咯烷酮是一种免疫调节剂和抗骨髓瘤化合物。

N-甲基-2-吡咯烷酮（NMP）是常见的溶剂和药物媒介。我们在cMYC驱动的骨髓瘤模型中发现了NMP意外的抗肿瘤和免疫调节活性。与此巧合的是，NMP被确定为乙酰赖氨酸模拟和候选溴结构域配体。因此，NMP处理的细胞表现出转录重叠与BET-bromodomain抑制，包括cMYC和IRF4的下调。NMP的免疫调节活性在低于BET的抑制浓度下发生，并且尽管与来那度胺具有表型相似性，但其抗骨髓瘤活性独立于IMiD靶标脑和Ikaros-1 / 3。因此，NMP的低亲和力和广谱溴结构域抑制作用介导了生物学上有效的，不依赖大脑的免疫调节，并以较高剂量直接通过BET拮抗作用靶向恶性细胞。这些数据表明，NMP是具有多效性抗骨髓瘤和免疫调节活性的功能性乙酰赖氨酸模拟物。我们的研究突出了NMP的潜在治疗益处，当前人类NMP暴露的后果以及需要重新评估将NMP用作“惰性”药物递送载体的科学文献的必要性。