Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors.
Journal
Translational oncology
ISSN: 1936-5233
Titre abrégé: Transl Oncol
Pays: United States
ID NLM: 101472619
Informations de publication
Date de publication:
Feb 2020
Feb 2020
Historique:
received:
27
09
2019
accepted:
30
09
2019
pubmed:
24
12
2019
medline:
24
12
2019
entrez:
24
12
2019
Statut:
ppublish
Résumé
Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models.
Identifiants
pubmed: 31869746
pii: S1936-5233(19)30390-0
doi: 10.1016/j.tranon.2019.09.013
pmc: PMC6931204
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
221-232Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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