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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8587151/ https://www.ncbi.nlm.nih.gov/pubmed/34770981 http://dx.doi.org/10.3390/molecules26216572 |
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author | Dao, Viet Hung Ourliac-Garnier, Isabelle Logé, Cédric McCarthy, Florence O. Bach, Stéphane da Silva, Teresinha Gonçalves Denevault-Sabourin, Caroline Thiéfaine, Jérôme Baratte, Blandine Robert, Thomas Gouilleux, Fabrice Brachet-Botineau, Marie Bazin, Marc-Antoine Marchand, Pascal |
author_facet | Dao, Viet Hung Ourliac-Garnier, Isabelle Logé, Cédric McCarthy, Florence O. Bach, Stéphane da Silva, Teresinha Gonçalves Denevault-Sabourin, Caroline Thiéfaine, Jérôme Baratte, Blandine Robert, Thomas Gouilleux, Fabrice Brachet-Botineau, Marie Bazin, Marc-Antoine Marchand, Pascal |
author_sort | Dao, Viet Hung |
collection | PubMed |
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[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC(50) 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 Galleria mellonella larvae testing for acute toxicity. |
format | Online Article Text |
id | pubmed-8587151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-85871512021-11-13 Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases Dao, Viet Hung Ourliac-Garnier, Isabelle Logé, Cédric McCarthy, Florence O. Bach, Stéphane da Silva, Teresinha Gonçalves Denevault-Sabourin, Caroline Thiéfaine, Jérôme Baratte, Blandine Robert, Thomas Gouilleux, Fabrice Brachet-Botineau, Marie Bazin, Marc-Antoine Marchand, Pascal Molecules Article 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[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC(50) 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 Galleria mellonella larvae testing for acute toxicity. MDPI 2021-10-30 /pmc/articles/PMC8587151/ /pubmed/34770981 http://dx.doi.org/10.3390/molecules26216572 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Dao, Viet Hung Ourliac-Garnier, Isabelle Logé, Cédric McCarthy, Florence O. Bach, Stéphane da Silva, Teresinha Gonçalves Denevault-Sabourin, Caroline Thiéfaine, Jérôme Baratte, Blandine Robert, Thomas Gouilleux, Fabrice Brachet-Botineau, Marie Bazin, Marc-Antoine Marchand, Pascal Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases |
title | 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_short | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8587151/ https://www.ncbi.nlm.nih.gov/pubmed/34770981 http://dx.doi.org/10.3390/molecules26216572 |
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