Dibenzofuran derivatives inspired from cercosporamide as dual inhibitors of Pim and CLK1 kinases

Abstract

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. Otherwise, Pim kinases were validated as valuable target for antitumor therapy. In that context, our combined efforts in natural product-inspired library generation and screening allowed us obtaining very promising dibenzo[b,d]furan derivatives derived from cercosporamide structure. Among them, the lead compound 44 was highlighted as potent Pim-1/2 kinases inhibitor with additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar concentration of anticancer potency towards MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure activity relationship and docking studies will be discussed and were supported by enzyme, cellular assays and Galleria mellonella larvae testing for acute toxicity investigations.