Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375–86. ©2017 AACR.

中文翻译：

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p97 抑制剂 CB-5083 是多发性骨髓瘤模型中蛋白质稳态的独特破坏者。

抑制 AAA ATP 酶 p97 最近被证明是一种靶向泛素蛋白酶体系统的新方法，而 CB-5083 是 p97 的一流抑制剂，已在一系列血液学和实体瘤模型。在这里，我们展示了 CB-5083 对多发性骨髓瘤细胞系和许多体内多发性骨髓瘤模型具有强大的活性。CB-5083 治疗与泛素化蛋白的积累、未折叠蛋白反应的诱导和细胞凋亡有关。CB-5083 降低多发性骨髓瘤细胞系和患者来源的多发性骨髓瘤细胞的活力，包括具有背景蛋白酶体抑制剂 (PI) 耐药性的细胞。CB-5083 具有独特的作用机制，可与 PI 很好地结合，这可能是由于转录因子 Nrf1 的 p97 依赖性逆转录易位所致，Nrf1 在暴露于 PI 后转录蛋白酶体亚基基因。使用临床相关多发性骨髓瘤模型进行的体内研究表明，单药 CB-5083 可抑制肿瘤生长并与多发性骨髓瘤标准治疗药物结合良好。我们的临床前数据证明了 CB-5083 在多种多发性骨髓瘤疾病模型中的疗效，并为在多发性骨髓瘤中作为单一疗法和联合疗法进行临床评估提供了依据。摩尔癌症治疗; 16(11); 2375-86。©2017 AACR。使用临床相关多发性骨髓瘤模型进行的体内研究表明，单药 CB-5083 可抑制肿瘤生长并与多发性骨髓瘤标准治疗药物结合良好。我们的临床前数据证明了 CB-5083 在多种多发性骨髓瘤疾病模型中的疗效，并为在多发性骨髓瘤中作为单一疗法和联合疗法进行临床评估提供了依据。摩尔癌症治疗; 16(11); 2375-86。©2017 AACR。使用临床相关多发性骨髓瘤模型进行的体内研究表明，单药 CB-5083 可抑制肿瘤生长并与多发性骨髓瘤标准治疗药物结合良好。我们的临床前数据证明了 CB-5083 在多种多发性骨髓瘤疾病模型中的疗效，并为在多发性骨髓瘤中作为单一疗法和联合疗法进行临床评估提供了依据。摩尔癌症治疗; 16(11); 2375-86。©2017 AACR。