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. 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.

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

“…The compounds exhibited low micromolar potency, highlighting their potential as promising candidates for targeting PIM-1/2 and CLK1 in anticancer treatments (Figure 11C). 134 4.4. Inhibitors from Natural Products.…”

“…These derivatives have displayed significant anticancer activity against MV4–11 (AML) cell lines, which express high levels of endogenous PIM-1/2 kinase. The compounds exhibited low micromolar potency, highlighting their potential as promising candidates for targeting PIM-1/2 and CLK1 in anticancer treatments (Figure C) …”