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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2021-10, Vol.26 (21), p.6572
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Acute toxicity; Animals; anticancer agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzofurans - chemical synthesis; Benzofurans - chemistry; Benzofurans - pharmacology; Binding sites; Biological activity; Carbon; Carcinoma; Cdc2 protein; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; cercosporamide; Chemical Sciences; Chemotherapy; CLK1 kinase; dibenzo[b,d]furan; Dibenzofuran; Drug Screening Assays, Antitumor; Humans; kinase inhibitors; Kinases; Larvae; Lead compounds; Leukemia; Ligands; Lung cancer; Models, Molecular; Molecular Structure; Moths; Natural products; Phenols; Pim kinases; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors; Proto-Oncogene Proteins c-pim-1 - metabolism; Toxicity testing; Tumor Cells, Cultured; Viruses
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26216572

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[ , ]furan derivatives derived from cercosporamide. Among them, lead compound was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC 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 larvae testing for acute toxicity.