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Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors

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 pediatr...

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Autores principales: Timme, Natalie, Han, Youjia, Liu, Shuai, Yosief, Hailemichael O., García, Heathcliff Dorado, Bei, Yi, Klironomos, Filippos, MacArthur, Ian C., Szymansky, Annabell, von Stebut, Jennifer, Bardinet, Victor, Dohna, Constantin, Künkele, Annette, Rolff, Jana, Hundsdörfer, Patrick, Lissat, Andrej, Seifert, Georg, Eggert, Angelika, Schulte, Johannes H., Zhang, Wei, Henssen, Anton G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931204/
https://www.ncbi.nlm.nih.gov/pubmed/31869746
http://dx.doi.org/10.1016/j.tranon.2019.09.013
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author Timme, Natalie
Han, Youjia
Liu, Shuai
Yosief, Hailemichael O.
García, Heathcliff Dorado
Bei, Yi
Klironomos, Filippos
MacArthur, Ian C.
Szymansky, Annabell
von Stebut, Jennifer
Bardinet, Victor
Dohna, Constantin
Künkele, Annette
Rolff, Jana
Hundsdörfer, Patrick
Lissat, Andrej
Seifert, Georg
Eggert, Angelika
Schulte, Johannes H.
Zhang, Wei
Henssen, Anton G.
author_facet Timme, Natalie
Han, Youjia
Liu, Shuai
Yosief, Hailemichael O.
García, Heathcliff Dorado
Bei, Yi
Klironomos, Filippos
MacArthur, Ian C.
Szymansky, Annabell
von Stebut, Jennifer
Bardinet, Victor
Dohna, Constantin
Künkele, Annette
Rolff, Jana
Hundsdörfer, Patrick
Lissat, Andrej
Seifert, Georg
Eggert, Angelika
Schulte, Johannes H.
Zhang, Wei
Henssen, Anton G.
author_sort Timme, Natalie
collection PubMed
description 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.
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spelling pubmed-69312042019-12-30 Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors Timme, Natalie Han, Youjia Liu, Shuai Yosief, Hailemichael O. García, Heathcliff Dorado Bei, Yi Klironomos, Filippos MacArthur, Ian C. Szymansky, Annabell von Stebut, Jennifer Bardinet, Victor Dohna, Constantin Künkele, Annette Rolff, Jana Hundsdörfer, Patrick Lissat, Andrej Seifert, Georg Eggert, Angelika Schulte, Johannes H. Zhang, Wei Henssen, Anton G. Transl Oncol Original article 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. Neoplasia Press 2019-12-21 /pmc/articles/PMC6931204/ /pubmed/31869746 http://dx.doi.org/10.1016/j.tranon.2019.09.013 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original article
Timme, Natalie
Han, Youjia
Liu, Shuai
Yosief, Hailemichael O.
García, Heathcliff Dorado
Bei, Yi
Klironomos, Filippos
MacArthur, Ian C.
Szymansky, Annabell
von Stebut, Jennifer
Bardinet, Victor
Dohna, Constantin
Künkele, Annette
Rolff, Jana
Hundsdörfer, Patrick
Lissat, Andrej
Seifert, Georg
Eggert, Angelika
Schulte, Johannes H.
Zhang, Wei
Henssen, Anton G.
Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors
title Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors
title_full Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors
title_fullStr Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors
title_full_unstemmed Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors
title_short Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors
title_sort small-molecule dual plk1 and brd4 inhibitors are active against preclinical models of pediatric solid tumors
topic Original article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931204/
https://www.ncbi.nlm.nih.gov/pubmed/31869746
http://dx.doi.org/10.1016/j.tranon.2019.09.013
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