title: Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism.
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.
authors.affiliation: 1] Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA [2] Genomic Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: C-M
authors.initials: CM
authors.lastname: Hu
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: J
authors.identifier: 0000000267428138
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: X E
authors.initials: XE
authors.lastname: Guo
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: X-L
authors.initials: XL
authors.lastname: Qiu
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Ngo
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chien
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: Y V
authors.initials: YV
authors.lastname: Wang
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: C Y
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Chemistry, University of California, Irvine, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Lopez
authors.affiliation: Department of Chemistry, University of California, Irvine, CA, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Chamberlin
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: E Y-H P
authors.initials: EY
authors.lastname: Lee
authors.affiliation: 1] 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.
authors.forename: W-H
authors.initials: WH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D007211:Indoles; D020128:Inhibitory Concentration 50; D008938:Mitosis / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D000072379:NIMA-Related Kinases; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D014631:Valerates
chemical_list: D001549:Benzamides; D003598:Cytoskeletal Proteins; D007211:Indoles; C120529:NDC80 protein, human; D009687:Nuclear Proteins; D013844:Thiazoles; D014631:Valerates; C510545:methyl 5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoate; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases