New Pyrimido-Indole Compound CD-160130 Preferentially Inhibits the KV11.1B Isoform and Produces Antileukemic Effects without Cardiotoxicity
New Pyrimido-Indole Compound CD-160130 Preferentially Inhibits the KV11.1B Isoform and Produces Antileukemic Effects without Cardiotoxicity
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DOI：
10.1124/mol.114.094920
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发表时间：
2015-02-01
影响因子：
3.6
通讯作者：
Arcangeli, Annarosa
中科院分区：
文献类型：
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作者：
Gasparoli, Luca;D'Amico, Massimo;Arcangeli, Annarosa
K（V）11.1（hERG 1）通道通常在人类癌症中过表达。在白血病中，K（V）11.1调节促进对化疗耐药性的促生存信号，提高了K（V）11.1抑制剂在治疗上有益的可能性。然而，由于K（V）11.1在心脏复极化中的作用，阻断这些通道可能导致心律失常。我们发现CD-160130（一种新型嘧啶并吲哚化合物）对K（V）11.1亚型B具有更高的阻断K（V）11.1通道的功效，其中IC 50（1.8 μ M）比K（V）11.1亚型A中观察到的IC 50低约10倍。在该浓度下，CD-160130对K（ir）2.1、K-V 1.3、K（v）1.5和K（Ca）3.1也有轻微影响。CD-160130在体外诱导白血病细胞凋亡，并能克服骨髓间充质干细胞（MSC）诱导的化疗耐药。这种效应是由MSC触发的生存信号通路的干扰引起的。在体内，CD-160130产生的抗白血病活性强于阿糖胞苷。与其非典型靶点特异性一致，CD-160130不与致炎性K（V）11.1阻断剂的主要结合位点（Phe 656孔残基）结合。重要的是，在豚鼠中，CD-160130既未改变分离心肌细胞的心脏动作电位形状，也未延长体内QT间期。此外，CD-160130对人骨髓源性细胞无骨髓毒性。因此，CD-160130是基于靶向K（V）11.1的有希望的首个尝试肿瘤治疗而无心脏毒性的化合物。由于白血病和心肌细胞倾向于表达不同比例的A和B K（V）11.1亚型，CD-160130的药理学特性可能至少部分取决于亚型特异性。
K(V)11.1 (hERG1) channels are often overexpressed in human cancers. In leukemias, K(V)11.1 regulates pro-survival signals that promote resistance to chemotherapy, raising the possibility that inhibitors of K(V)11.1 could be therapeutically beneficial. However, because of the role of K(V)11.1 in cardiac repolarization, blocking these channels may cause cardiac arrhythmias. We show that CD-160130, a novel pyrimido-indole compound, blocks K(V)11.1 channels with a higher efficacy for the K(V)11.1 isoform B, in which the IC50 (1.8 mu M) was approximately 10-fold lower than observed in K(V)11.1 isoform A. At this concentration, CD-160130 also had minor effects on K(ir)2.1, K-V 1.3, K(v)1.5, and K(Ca)3.1. In vitro, CD-160130 induced leukemia cell apoptosis, and could overcome bone marrow mesenchymal stromal cell (MSC)-induced chemoresistance. This effect was caused by interference with the survival signaling pathways triggered by MSCs. In vivo, CD-160130 produced an antileukemic activity, stronger than that caused by cytarabine. Consistent with its atypical target specificity, CD-160130 did not bind to the main binding site of the arrhythmogenic K(V)11.1 blockers (the Phe656 pore residue). Importantly, in guinea pigs CD-160130 produced neither alteration of the cardiac action potential shape in dissociated cardiomyocytes nor any lengthening of the QT interval in vivo. Moreover, CD-160130 had no myelotoxicity on human bone marrow-derived cells. Therefore, CD-160130 is a promising first-in-class compound to attempt oncologic therapy without cardiotoxicity, based on targeting K(V)11.1. Because leukemia and cardiac cells tend to express different ratios of the A and B K(V)11.1 isoforms, the pharmacological properties of CD-160130 may depend, at least in part, on isoform specificity.