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Targeted Protein Upregulation of STING for Boosting the Efficacy of Immunotherapy

Herein, we demonstrated that targeted protein upregulation of STING potentiates immunotherapy agents. Using a luminescence-based cellular assay, we discovered a novel protein-protein interaction modulator, SB24011, that inhibited the STING-TRIM29 E3 ligase interaction and upregulated cellular STING levels. As a result, SB24011 boosted STING immunity and improved the in vivo efficacy of immunotherapy with a STING agonist and an anti-PD-1 antibody.


Modulating target proteins via the ubiquitin-proteasome system has recently expanded the scope of pharmacological inventions. Stimulator of interferon genes (STING) is an auspicious target for immunotherapy. Seminal studies envisioned the importance of STING as well as the utility of its agonists in immunotherapy outcomes. Herein, we suggest UPPRIS (upregulation of target proteins by protein-protein interaction strategy) to pharmacologically increase cellular STING levels for improved immunotherapy. We discovered the small molecule SB24011 that inhibits STING-TRIM29 E3 ligase interaction, thus blocking TRIM29-induced degradation of STING. SB24011 enhanced STING immunity by upregulating STING protein levels, which robustly potentiated the immunotherapy efficacy of STING agonist and anti-PD-1 antibody via systemic anticancer immunity. Overall, we demonstrated that targeted protein upregulation of STING can be a promising approach for immuno-oncology.

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