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

Viet Hung Dao1, Isabelle Ourliac-Garnier1, Cédric Logé1

  • 1Cibles et Médicaments des Infections et du Cancer, IICiMed, EA 1155, Université de Nantes, 44000 Nantes, France.

Molecules (Basel, Switzerland)
|November 13, 2021
PubMed

Insights

Researchers developed novel dibenzofuran compounds that inhibit Pim kinases, crucial targets in cancer therapy. Lead compound 44 shows potent anticancer activity against AML cells and low toxicity, offering a promising new therapeutic avenue.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Pharmacology

Background:

  • Pim kinases are overexpressed in various cancers, promoting cell proliferation and survival, making them validated targets for antitumor therapy.
  • Natural product-inspired drug discovery offers a promising avenue for identifying novel anticancer agents.

Purpose of the Study:

  • To design, synthesize, and evaluate novel dibenzofuran derivatives as potent Pim kinase inhibitors.
  • To investigate the anticancer activity and toxicity profile of lead compound 44.

Main Methods:

  • Synthesis of dibenzofuran derivatives inspired by natural products.
  • Enzyme inhibition assays to determine IC50 values for Pim-1/2 and CLK1 kinases.
  • Cellular assays using MV4-11 (AML) cell line to assess anticancer potency.
  • Acute toxicity testing in Galleria mellonella larvae.

Main Results:

  • Lead compound 44, a dibenzofuran derivative, demonstrated potent inhibition of Pim-1/2 kinases with nanomolar IC50 values.
  • Compound 44 also inhibited CLK1 (cdc2-like kinases 1) with nanomolar potency.
  • Anticancer activity was observed in the MV4-11 AML cell line with low micromolar potency.
  • Compound 44 exhibited low acute toxicity in Galleria mellonella larvae.

Conclusions:

  • Novel dibenzofuran derivatives, exemplified by compound 44, are potent inhibitors of Pim kinases and exhibit promising anticancer activity.
  • Compound 44 represents a potential lead for developing new therapies against hematological malignancies and solid carcinomas.
  • The natural product-inspired approach is effective for discovering novel kinase inhibitors with favorable toxicity profiles.
Keywords:
CLK1 kinasePim kinasesanticancer agentscercosporamidedibenzo[b,d]furankinase inhibitors

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