The New Pyrimido-indole Compound CD-160130 Preferentially Inhibits the KV11.1B Isoform and Produces Antileukemic Effects Without Cardio-toxicity

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.