Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases

Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our...

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Autores principales:	Viet Hung Dao, Isabelle Ourliac-Garnier, Cédric Logé, Florence O. McCarthy, Stéphane Bach, Teresinha Gonçalves da Silva, Caroline Denevault-Sabourin, Jérôme Thiéfaine, Blandine Baratte, Thomas Robert, Fabrice Gouilleux, Marie Brachet-Botineau, Marc-Antoine Bazin, Pascal Marchand
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cercosporamide dibenzo[<i>b</i>,<i>d</i>]furan Pim kinases CLK1 kinase kinase inhibitors anticancer agents Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/8fc82c9ac56046e4ad1322814a4aabf7
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spelling	oai:doaj.org-article:8fc82c9ac56046e4ad1322814a4aabf72021-11-11T18:33:15ZDibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases10.3390/molecules262165721420-3049https://doaj.org/article/8fc82c9ac56046e4ad1322814a4aabf72021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6572https://doaj.org/toc/1420-3049Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[<i>b</i>,<i>d</i>]furan derivatives derived from cercosporamide. Among them, lead compound <b>44</b> was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC<sub>50</sub> value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure–activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and <i>Galleria mellonella</i> larvae testing for acute toxicity.Viet Hung DaoIsabelle Ourliac-GarnierCédric LogéFlorence O. McCarthyStéphane BachTeresinha Gonçalves da SilvaCaroline Denevault-SabourinJérôme ThiéfaineBlandine BaratteThomas RobertFabrice GouilleuxMarie Brachet-BotineauMarc-Antoine BazinPascal MarchandMDPI AGarticlecercosporamidedibenzo[<i>b</i>,<i>d</i>]furanPim kinasesCLK1 kinasekinase inhibitorsanticancer agentsOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6572, p 6572 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cercosporamide dibenzo[<i>b</i>,<i>d</i>]furan Pim kinases CLK1 kinase kinase inhibitors anticancer agents Organic chemistry QD241-441
spellingShingle	cercosporamide dibenzo[<i>b</i>,<i>d</i>]furan Pim kinases CLK1 kinase kinase inhibitors anticancer agents Organic chemistry QD241-441 Viet Hung Dao Isabelle Ourliac-Garnier Cédric Logé Florence O. McCarthy Stéphane Bach Teresinha Gonçalves da Silva Caroline Denevault-Sabourin Jérôme Thiéfaine Blandine Baratte Thomas Robert Fabrice Gouilleux Marie Brachet-Botineau Marc-Antoine Bazin Pascal Marchand Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases
description	Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[<i>b</i>,<i>d</i>]furan derivatives derived from cercosporamide. Among them, lead compound <b>44</b> was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC<sub>50</sub> value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure–activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and <i>Galleria mellonella</i> larvae testing for acute toxicity.
format	article
author	Viet Hung Dao Isabelle Ourliac-Garnier Cédric Logé Florence O. McCarthy Stéphane Bach Teresinha Gonçalves da Silva Caroline Denevault-Sabourin Jérôme Thiéfaine Blandine Baratte Thomas Robert Fabrice Gouilleux Marie Brachet-Botineau Marc-Antoine Bazin Pascal Marchand
author_facet	Viet Hung Dao Isabelle Ourliac-Garnier Cédric Logé Florence O. McCarthy Stéphane Bach Teresinha Gonçalves da Silva Caroline Denevault-Sabourin Jérôme Thiéfaine Blandine Baratte Thomas Robert Fabrice Gouilleux Marie Brachet-Botineau Marc-Antoine Bazin Pascal Marchand
author_sort	Viet Hung Dao
title	Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases
title_short	Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases
title_full	Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases
title_fullStr	Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases
title_full_unstemmed	Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases
title_sort	dibenzofuran derivatives inspired from cercosporamide as dual inhibitors of pim and clk1 kinases
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/8fc82c9ac56046e4ad1322814a4aabf7
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Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases

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