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

Autor: Caroline Denevault-Sabourin, Marc-Antoine Bazin, Isabelle Ourliac-Garnier, Florence O. McCarthy, Marie Brachet-Botineau, Teresinha Gonçalves da Silva, Blandine Baratte, Jérôme Thiéfaine, Viet Hung Dao, Thomas Robert, Stéphane Bach, Cédric Logé, Fabrice Gouilleux, Pascal Marchand
Přispěvatelé: Cibles et médicaments de l'infection, de l'immunité et du cancer (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), University College Cork (UCC), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Plate-forme de criblage d'inhibiteurs de protéines kinases=Kinase Inhibitor Specialized Screening facility (KISSf), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx) (LNOx), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Tours (UT)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Rok vydání: 2021
Předmět:
Models
Molecular
Pharmaceutical Science
Organic chemistry
Moths
01 natural sciences
Analytical Chemistry
CLK1
Docking (dog)
QD241-441
hemic and lymphatic diseases
Drug Discovery
Murine leukemia virus
CLK1 kinase
Tumor Cells
Cultured
kinase inhibitors
cercosporamide
chemistry.chemical_classification
0303 health sciences
Pim kinases
biology
Molecular Structure
Kinase
Protein-Tyrosine Kinases
3. Good health
Chemistry (miscellaneous)
dibenzo[b
d]furan
Molecular Medicine
Cell Survival
Context (language use)
Antineoplastic Agents
Protein Serine-Threonine Kinases
Article
03 medical and health sciences
anticancer agents
Proto-Oncogene Proteins c-pim-1
[CHIM]Chemical Sciences
Animals
Humans
Physical and Theoretical Chemistry
Protein Kinase Inhibitors
030304 developmental biology
Benzofurans
Cell Proliferation
010405 organic chemistry
Cell growth
biology.organism_classification
0104 chemical sciences
Enzyme
chemistry
Cell culture
Cancer research
Drug Screening Assays
Antitumor
Zdroj: Molecules
Molecules, MDPI, 2021, 26 (21), pp.6572. ⟨10.3390/molecules26216572⟩
Molecules, Vol 26, Iss 6572, p 6572 (2021)
Volume 26
Issue 21
ISSN: 1420-3049
DOI: 10.3390/molecules26216572⟩
Popis: 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 IC50 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.
Databáze: OpenAIRE
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