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Small-molecule dual PLK1 and BRD4 inhibitors are active against preclinical models of pediatric solid tumors

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Item Type:Article
Title:Small-molecule dual PLK1 and BRD4 inhibitors are active against preclinical models of pediatric solid tumors
Creators Name:Timme, N. and Han, Y. and Liu, S. and Yosief, H.O. and García, H.D. and Bei, Y. and Klironomos, F. and MacArthur, I.C. and Szymansky, A. and von Stebut, J. and Bardinet, V. and Dohna, C. and Künkele, A. and Rolff, J. and Hundsdörfer, P. and Lissat, A. and Seifert, G. and Eggert, A. and Schulte, J.H. and Zhang, W. and Henssen, A.G.
Abstract: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.
Source:Translational Oncology
Publisher:Elsevier / Neoplasia Press
Page Range:221-232
Date:February 2020
Official Publication:https://doi.org/10.1016/j.tranon.2019.09.013
PubMed:View item in PubMed

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