Evidence map›Paper›PMID 24662830›Full record

ArticleOncogene2015

Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism.

C-M Hu, J Zhu, X E Guo, W Chen, X-L Qiu, B Ngo, R Chien, Y V Wang, C Y Tsai, G Wu and 5 more

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

Article in Oncogene, 2015. 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 14% 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, 57 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
  4. Role of NEK2 in tumorigenesis and tumor progression.Trends in molecular medicine · 2025
    Review
  5. The NIMA-related kinase family and cancer.Frontiers in oncology · 2025
    Review
  6. Article
  7. The two sides of chromosomal instability: drivers and brakes in cancer.Signal transduction and targeted therapy · 2024
    Review
  8. Article
  9. Thiazole, Isatin and Phthalimide Derivatives TestedCurrent medicinal chemistry · 2024
    Review
  10. Article
  11. Article
  12. Review
  13. Review
  14. Article
  15. Article
  16. Review
  17. Article
  18. Article
  19. Article
  20. Article
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 2 institutions in 2 countries.

C-M Hu1] Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA [2] Genomic Research Center, Academia Sinica, Taipei, Taiwan.
J ZhuDepartment of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.ORCID 0000000267428138
X E GuoDepartment of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
W ChenDepartment of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
X-L QiuDepartment of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
B NgoDepartment of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
R ChienDepartment of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
Y V WangDepartment of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
C Y TsaiDepartment of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
G WuDepartment of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
Y KimDepartment of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
R LopezDepartment of Chemistry, University of California, Irvine, CA, USA.
A R ChamberlinDepartment of Chemistry, University of California, Irvine, CA, USA.
E Y-H P LeeDepartment of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
W-H Lee1] Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA [2] Genomic Research Center, Academia Sinica, Taipei, Taiwan [3] Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
University of California, Irvine · USChina Medical University · TW

Funding

Hec1 Network as Molecular Therapeutic TargetsR01CA107568 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI LEE, WEN-HWA · 2004 to 2014
$3.6M
NCI NIH HHS CA107568NCI NIH HHS R01 CA107568
6 · The paper itself

Abstract

Hec1 (highly expressed in cancer 1) or Nek2 (NIMA-related kinase 2) is often overexpressed in cancers with poor prognosis. Both are critical mitotic regulators, and phosphorylation of Hec1 S165 by Nek2 is required for proper chromosome segregation. Therefore, inactivation of Hec1 and Nek2 by targeting their interaction with small molecules represents an ideal strategy for tackling these types of cancers. Here we showed that new derivatives of INH (inhibitor for Nek2 and Hec1 binding) bind to Hec1 at amino acids 394-408 on W395, L399 and K400 residues, effectively blocking Hec1 phosphorylation on S165 by Nek2, and killing cancer cells at the nanomolar range. Mechanistically, the D-box (destruction-box) region of Nek2 specifically binds to Hec1 at amino acids 408-422, immediately adjacent to the INH binding motif. Subsequent binding of Nek2 to INH-bound Hec1 triggered proteasome-mediated Nek2 degradation, whereas the Hec1 binding defective Nek2 mutant, Nek2 R361L, resisted INH-induced Nek2 degradation. This finding unveils a novel drug-action mechanism where the binding of INHs to Hec1 forms a virtual death-trap to trigger Nek2 degradation and eventually cell death. Furthermore, analysis of the gene expression profiles of breast cancer patient samples revealed that co-elevated expressions of Hec1 and Nek2 correlated with the shortest survival. Treatment of mice with this kind of tumor with INHs significantly suppressed tumor growth without obvious toxicity. Taken together, the new INH derivatives are suitable for translation into clinical application.

Indexed as

AnimalsBenzamidesBinding SitesCell Line, TumorCytoskeletal ProteinsDisease Models, AnimalDisease ProgressionGene ExpressionHeterograftsHumansIndolesInhibitory Concentration 50MitosisModels, MolecularMolecular ConformationNeoplasmsBenzamidesCytoskeletal ProteinsIndolesmethyl 5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoateNDC80 protein, humanNEK2 protein, humanNIMA-Related KinasesNuclear ProteinsProtein Serine-Threonine KinasesThiazolesValerates

Identifiers

PMID24662830
PMCPMC4175300
OpenAlexW2046333895

What OpenQuestion holds

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Registered trials

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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.