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Research ArticleToxicology

A p97/Valosin-Containing Protein Inhibitor Drug CB-5083 Has a Potent but Reversible Off-Target Effect on Phosphodiesterase-6

Henri Leinonen, Cheng Cheng, Marja Pitkänen, Christopher L. Sander, Jianye Zhang, Sama Saeid, Teemu Turunen, Alyaa Shmara, Lan Weiss, Lac Ta, Timothy Ton, Ari Koskelainen, Jesse D. Vargas, Virginia Kimonis and Krzysztof Palczewski
Journal of Pharmacology and Experimental Therapeutics July 2021, 378 (1) 31-41; DOI: https://doi.org/10.1124/jpet.120.000486
Henri Leinonen
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Cheng Cheng
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Marja Pitkänen
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Christopher L. Sander
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Jianye Zhang
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Sama Saeid
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Teemu Turunen
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Alyaa Shmara
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Lan Weiss
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Lac Ta
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Timothy Ton
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Ari Koskelainen
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Jesse D. Vargas
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Virginia Kimonis
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Krzysztof Palczewski
Gavin Herbert Eye Institute, Department of Ophthalmology (H.L., C.L.S., J.Z., K.P.), Department of Physiology & Biophysics (K.P.), Department of Chemistry (K.P.), and Division of Genetics and Genomic Medicine, Department of Pediatrics (C.C., A.S., L.W., L.T., T.T., V.K.), University of California Irvine, Irvine, California Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio (C.L.S.); Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland (M.P., S.S., T.T., A.K.); and Cleave Therapeutics, Inc., San Francisco, California
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Abstract

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 re-evaluation of CB-5083 as a clinical therapeutic agent. We recommend preclinical ERG recordings as a routine drug safety screen.

SIGNIFICANCE STATEMENT This 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.

Footnotes

    • Received December 26, 2020.
    • Accepted April 29, 2021.
  • No author has an actual or perceived conflict of interest with the contents of this article.

  • H.L. was supported by research grants from the Knights Templar Eye Foundation, Silmä- ja kudospankkisäätiö (Eye and Tissue Bank Foundation), the Finnish Cultural Foundation, and the Orion Research Foundation. K.P was supported by National Institutes of Health National Eye Institute (NEI) [Grants R01EY009339-27 and R24EY027283-01]. K.P is the Irving H. Leopold Chair of Ophthalmology and CSO of Polgenix Inc. The authors also acknowledge support from a Research to Prevent Blindness unrestricted grant to the Department of Ophthalmology, University of California, Irvine.

  • https://doi.org/10.1124/jpet.120.000486.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 378 (1)
Journal of Pharmacology and Experimental Therapeutics
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1 Jul 2021
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Research ArticleToxicology

Off-Target Deactivation of PDE6 by VCP Inhibitor CB-5083

Henri Leinonen, Cheng Cheng, Marja Pitkänen, Christopher L. Sander, Jianye Zhang, Sama Saeid, Teemu Turunen, Alyaa Shmara, Lan Weiss, Lac Ta, Timothy Ton, Ari Koskelainen, Jesse D. Vargas, Virginia Kimonis and Krzysztof Palczewski
Journal of Pharmacology and Experimental Therapeutics July 1, 2021, 378 (1) 31-41; DOI: https://doi.org/10.1124/jpet.120.000486

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Research ArticleToxicology

Off-Target Deactivation of PDE6 by VCP Inhibitor CB-5083

Henri Leinonen, Cheng Cheng, Marja Pitkänen, Christopher L. Sander, Jianye Zhang, Sama Saeid, Teemu Turunen, Alyaa Shmara, Lan Weiss, Lac Ta, Timothy Ton, Ari Koskelainen, Jesse D. Vargas, Virginia Kimonis and Krzysztof Palczewski
Journal of Pharmacology and Experimental Therapeutics July 1, 2021, 378 (1) 31-41; DOI: https://doi.org/10.1124/jpet.120.000486
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