title: New pyrimido-indole compound CD-160130 preferentially inhibits the KV11.1B isoform and produces antileukemic effects without cardiotoxicity.
abstract: KV11.1 (hERG1) channels are often overexpressed in human cancers. In leukemias, KV11.1 regulates pro-survival signals that promote resistance to chemotherapy, raising the possibility that inhibitors of KV11.1 could be therapeutically beneficial. However, because of the role of KV11.1 in cardiac repolarization, blocking these channels may cause cardiac arrhythmias. We show that CD-160130, a novel pyrimido-indole compound, blocks KV11.1 channels with a higher efficacy for the KV11.1 isoform B, in which the IC50 (1.8 μM) was approximately 10-fold lower than observed in KV11.1 isoform A. At this concentration, CD-160130 also had minor effects on Kir2.1, KV 1.3, Kv1.5, and KCa3.1. 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 KV11.1 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 KV11.1. Because leukemia and cardiac cells tend to express different ratios of the A and B KV11.1 isoforms, the pharmacological properties of CD-160130 may depend, at least in part, on isoform specificity.
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.).
authors.forename: Luca
authors.initials: L
authors.lastname: Gasparoli
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.).
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Amico
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.).
authors.forename: Marika
authors.initials: M
authors.lastname: Masselli
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.).
authors.forename: Serena
authors.initials: S
authors.lastname: Pillozzi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.).
authors.forename: Rachel
authors.initials: R
authors.lastname: Caves
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.).
authors.forename: Rawan
authors.initials: R
authors.lastname: Khuwaileh
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Tiedke
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.).
authors.forename: Kenneth
authors.initials: K
authors.lastname: Mugridge
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.).
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pratesi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.).
authors.forename: John S
authors.initials: JS
authors.lastname: Mitcheson
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.).
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Becchetti
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.) annarosa.arcangeli@unifi.it.
authors.forename: Annarosa
authors.initials: A
authors.lastname: Arcangeli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D054715:Cardiotoxins; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015448:Leukemia, B-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; C000596338:CD-160130; D054715:Cardiotoxins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007211:Indoles; C000606913:KCNH2 protein, human; D020033:Protein Isoforms; D011743:Pyrimidines; D011744:Pyrimidinones