Novel Pyrrolopyrimidines as Inhibitors of CLK4 and HER2: Targeting Promising Anticancer Pathways.

Abstract

Background: Dysregulated cellular signaling pathways involving protein kinases are critically implicated in cancer development. Consequently, protein kinases have emerged as key targets for novel anticancer therapies. A range of kinase inhibitors, including small molecules and monoclonal antibodies, has been developed. Although early strategies focused on achieving high specificity to minimize adverse effects, resistance to these targeted therapies has limited their effectiveness. As a result, broader-spectrum inhibitors that act on multiple cancer-related kinases are now considered more promising therapeutic options.

Objective: We developed twenty-five new pyrrolopyrimidine derivatives featuring diverse substitution patterns to assess their potential as small-molecule inhibitors of the protein kinases CLK4 and HER2, both of which are significant therapeutic targets in metastatic breast cancer.

Method: Pyrrolopyrimidine derivatives were synthesized and purified by column chromatography. Their protein kinase inhibitory activity was evaluated through a radioactive ATPcompetition assay.

Results: The compounds were obtained through a multi-step synthetic procedure, concluding with substitution reactions. The effects of different substituents on the inhibitory properties of the observed protein kinases are analyzed and discussed.

Conclusion: Aniline-substituted derivatives exhibited the most potent activities, which were further modulated by N-substituted pyrroles. Consequently, we identified both selective and dual inhibitors of the target kinases, demonstrating activity in the nanomolar range.