Evidence map›Paper›PMID 33931547›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2021

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 and 5 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of pharmacology and experimental therapeutics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.

0numbers the graph read from it
0cells of the map it votes in
36citing papers in PubMed
2.1field-weighted citation impact, top 12% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

36 citing papers in PubMed, 42 citations in OpenAlex.

  1. Review
  2. Article
  3. Article
  4. Article
  5. Article
  6. Article
  7. Article
  8. Article
  9. Review
  10. Article
  11. Article
  12. Article
  13. A genome-scale drug discovery pipeline uncovers therapeutic targets and a unique p97 allosteric binding site inProceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  14. Oncotarget · 2025
    Article
  15. Article
  16. Review
  17. Article
  18. Design and Synthesis of Novel 5,6,7,8-Tetrahydropyrido[2,3-Drug design, development and therapy · 2025
    Article
  19. Article
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors at 3 institutions in 2 countries.

Henri LeinonenGavin 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 (J.D.V.) kpalczew@uci.edu hleinone@uci.edu vkimonis@uci.edu.
Cheng ChengGavin 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 (J.D.V.).
Marja PitkänenGavin 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 (J.D.V.).
Christopher L SanderGavin 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 (J.D.V.).
Jianye ZhangGavin 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 (J.D.V.).
Sama SaeidGavin 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 (J.D.V.).
Teemu TurunenGavin 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 (J.D.V.).
Alyaa ShmaraGavin 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 (J.D.V.).
Lan WeissGavin 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 (J.D.V.).
Lac TaGavin 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 (J.D.V.).
Timothy TonGavin 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 (J.D.V.).
Ari KoskelainenGavin 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 (J.D.V.).
Jesse D VargasGavin 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 (J.D.V.).
Virginia KimonisGavin 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 (J.D.V.) kpalczew@uci.edu hleinone@uci.edu vkimonis@uci.edu.
Krzysztof PalczewskiGavin 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 (J.D.V.) kpalczew@uci.edu hleinone@uci.edu vkimonis@uci.edu.
University of California, Irvine · USAalto University · FICase Western Reserve University · US

Funding

STRUCTURAL STUDIES OF ARRESTINSR01EY009339 · NEI · UNIVERSITY OF WASHINGTON · PI KISER, PHILIP DAVID, PALCZEWSKI, KRZYSZTOF · 1992 to 2025
$16.0M
Use of systems pharmacology to prevent rod and cone photoreceptor degenerationR24EY027283 · NEI · UNIVERSITY OF CALIFORNIA-IRVINE · PI PALCZEWSKI, KRZYSZTOF · 2017 to 2021
$7.9M
The complex role of phosphodiesterase 6 in rod photoreceptor health and functionR01EY030873 · NEI · UNIVERSITY OF CALIFORNIA-IRVINE · PI Krzysztof Palczewski · 2020 to 2026
$3.5M
High-fat diet rescues lethality of homozygous knock-in R155H VCP myopathic miceR21AR063360 · NIAMS · UNIVERSITY OF CALIFORNIA-IRVINE · PI KIMONIS, VIRGINIA EUNICE · 2012 to 2013
$399k
Preclinical Studies in Myopathy and ALS with VCP inhibitor CB5083R21AR074746 · NIAMS · UNIVERSITY OF CALIFORNIA-IRVINE · PI KIMONIS, VIRGINIA EUNICE · 2019 to 2020
$374k
NEI NIH HHS R01 EY009339NEI NIH HHS R01 EY030873NEI NIH HHS R24 EY027283NIAMS NIH HHS R21 AR063360NIAMS NIH HHS R21 AR074746
6 · The paper itself

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.

Indexed as

AnimalsCattleCyclic Nucleotide Phosphodiesterases, Type 6Dose-Response Relationship, DrugElectroretinographyFemaleIndolesMaleMiceMice, Inbred C57BLMice, TransgenicPhotic StimulationPyrimidinesRetinaValosin Containing ProteinCB-5083Cyclic Nucleotide Phosphodiesterases, Type 6IndolesPyrimidinesValosin Containing ProteinVcp protein, mouse

Identifiers

PMID33931547
PMCPMC8456514
OpenAlexW3158627946

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.