Design,synthesis and biological evaluation of IRAK4 degraders based on proteolytic targeting chimera
Objective To design and synthesize interleukin-1 receptor-associated kinase 4(IRAK4)degraders with antitumor activity.Methods The target compounds were synthesized by ligating IRAK4 protein ligand and E3 ligase ligand with different types and lengths of linker chains.Their structures were confirmed by MS spectroscopy and 1H NMR spectroscopy.Large B-cell lymphoma cells OCI-LY10 were used as the test cell line,and the anti-tumor activity of the synthesized target compounds was evaluated in vitro and the degradation of IRAK4 was tested.Results Totally 9 degraders targeting IRAK4 were synthesized,and the activity test showed that the target compounds inhibited the proliferation of large B-cell lymphoma cells OCI-LY10 cells,among which compoundsⅢ,Ⅶ,Ⅷ,and Ⅸ had strong degradation against IRAK4,with the DC50 value at 1～10 nmol·L-1.Conclusion The use of protein degradation targeting chimera technology to inhibit the proliferation of tumor cells through the degradation of IRAK4 is worthy of further study.
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