A p97/Valosin-Containing Protein Inhibitor Drug CB-5083 Has a Potent but Reversible Off-Target Effect on Phosphodiesterase-6
A p97/Valosin-Containing Protein Inhibitor Drug CB-5083 Has a Potent but Reversible Off-Target Effect on Phosphodiesterase-6
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DOI：
10.1124/jpet.120.000486
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发表时间：
2021-07-01
影响因子：
3.5
通讯作者：
Palczewski, Krzysztof
中科院分区：
文献类型：
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作者：
Leinonen, Henri;Cheng, Cheng;Palczewski, Krzysztof
CB-5083是一种p97/valosin-containing蛋白（VCP）的抑制剂，其I期癌症试验因对视力的不良影响而终止，如恐惧症和色觉障碍。较低剂量的CB-5083可以对抗早发性佩吉特病和额颞叶痴呆的包涵体肌病或VCP功能获得性突变引起的多系统蛋白质病。我们假设癌症试验中的视力损害是由于CB-5083对磷酸二酯酶（PDE）-6的抑制，PDE-6介导光感受器中的信号转导。为了验证我们的假设，我们使用了在体内和离体视网膜电图（ERG）在小鼠和牛杆外段（ROS）提取物的PDE 6活性测定。此外，组织学和光学相干断层扫描用于评估CB-5083的长期眼毒性。CB-5083单次给药导致ERG信号明显恶化，特别是在光反应动力学方面。已知PDE抑制剂西地那非、他达拉非、伐地那非和扎普司特的类似记录表明，只有伐地那非对体内ERG信号的影响与CB-5083一样强。在生化试验中，CB-5083抑制PDE 6活性的效力高于西地那非，但低于伐地那非。离体ERG显示CB-5083的PDE 6抑制常数为80 nM，比西地那非小7倍。最后，我们表明CB-5083对视觉功能的抑制作用是可逆的，并且其长期给药不会导致老年VCP疾病模型小鼠的永久性视网膜异常。我们的研究结果保证CB-5083作为临床治疗剂的重新评估。我们建议临床前ERG记录作为常规药物safety screen.Significance StatementThis报告支持使用valosin含蛋白（VCP）抑制剂药物，CB-5083，用于治疗神经肌肉VCP疾病，尽管CB-5083的癌症治疗的初始临床失败，由于视力的副作用。数据显示CB-5083对磷酸二酯酶-6（视网膜感光器功能中的必需酶）显示剂量依赖性但可逆的抑制作用，但对视网膜功能或结构没有长期影响。
CB-5083 is an inhibitor of p97/valosin-containing protein (VCP), for which phase I trials for cancer were terminated because of adverse effects on vision, such as photophobia and dyschromatopsia. Lower dose CB-5083 could combat inclusion body myopathy with early-onset Paget disease and frontotemporal dementia or multisystem proteinopathy caused by gain-of-function mutations in VCP. We hypothesized that the visual impairment in the cancer trial was due to CB-5083's inhibition of phosphodiesterase (PDE)-6, which mediates signal transduction in photoreceptors. To test our hypothesis, we used in vivo and ex vivo electroretinography (ERG) in mice and a PDE6 activity assay of bovine rod outer segment (ROS) extracts. Additionally, histology and optical coherence tomography were used to assess CB-5083's long-term ocular toxicity. A single administration of CB-5083 led to robust ERG signal deterioration, specifically in photoresponse kinetics. Similar recordings with known PDE inhibitors sildenafil, tadalafil, vardenafil, and zaprinast showed that only vardenafil had as strong an effect on the ERG signal in vivo as did CB-5083. In the biochemical assay, CB-5083 inhibited PDE6 activity with a potency higher than sildenafil but lower than that of vardenafil. Ex vivo ERG revealed a PDE6 inhibition constant of 80 nM for CB-5083, which is 7-fold smaller than that for sildenafil. Finally, we showed that the inhibitory effect of CB-5083 on visual function is reversible, and its chronic administration does not cause permanent retinal anomalies in aged VCP-disease model mice. Our results warrant reevaluation of CB-5083 as a clinical therapeutic agent. We recommend preclinical ERG recordings as a routine drug safety screen.SIGNIFICANCE STATEMENTThis report supports the use of a valosin-containing protein (VCP) inhibitor drug, CB-5083, for the treatment of neuromuscular VCP disease despite CB-5083's initial clinical failure for cancer treatment due to side effects on vision. The data show that CB-5083 displays a dose-dependent but reversible inhibitory action on phosphodiesterase-6, an essential enzyme in retinal photoreceptor function, but no long-term consequences on retinal function or structure.