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。

最近显示，抑制AAA ATPase p97是靶向泛素蛋白酶体系统的一种新方法，而pB的首批抑制剂CB-5083已在多种血液学和肿瘤学领域均表现出广泛的抗肿瘤活性。实体瘤模型。在这里，我们显示CB-5083具有针对多发性骨髓瘤细胞系和许多体内多发性骨髓瘤模型的强大活性。CB-5083的治疗与泛素化蛋白的积累，未折叠蛋白应答的诱导和细胞凋亡有关。CB-5083降低了多发性骨髓瘤细胞系和患者来源的多发性骨髓瘤细胞（包括具有背景蛋白酶体抑制剂（PI）耐药性的细胞）的活力。CB-5083具有独特的作用机制，可与PI很好地结合在一起，这可能归因于转录因子Nrf1的p97依赖性逆转，后者在暴露于PI后会转录蛋白酶体亚基基因。使用临床相关的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护理剂良好结合。我们的临床前数据证明了CB-5083在几种多发性骨髓瘤疾病模型中的疗效，并为单药治疗和多发性骨髓瘤联合治疗的临床评估提供了依据。分子癌疗法；16（11）; 2375–86。©2017 AACR。使用临床相关的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护理剂良好结合。我们的临床前数据证明了CB-5083在几种多发性骨髓瘤疾病模型中的疗效，并为单药治疗和多发性骨髓瘤联合治疗的临床评估提供了依据。分子癌疗法；16（11）; 2375–86。©2017 AACR。使用临床相关的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护理剂良好结合。我们的临床前数据证明了CB-5083在几种多发性骨髓瘤疾病模型中的疗效，并为单药治疗和多发性骨髓瘤联合治疗的临床评估提供了依据。分子癌疗法；16（11）; 2375–86。©2017 AACR。