Page 68 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-37]

Reversing the recurrent loss of STING via negative feedback

blockade for efficient cancer immunotherapy

Wansang Cho¹, Yoona Choi¹, Seung Bum Park¹˙²

¹Department of Chemistry, Seoul National University, Seoul 08826, Korea, ²Department of Biophysics and Chemical

Biology, Seoul National University, Seoul 08826, Korea

As cancer immunotherapy has been emerged as a new pillar of cancer therapy, diverse strategies are suggested
based on modulating host immunity for cancer treatment. STING, which is at the center of anti-DNA virus immunity,

is one of well-studied target for cancer immunotherapy. STING is activated by small molecule-like innate ligand,

cyclic dinucleotide (CDN). CDN analogs are suggested as new cancer immunotherapy agents that activates host
immune system. Intratumoral injection of CDN augments local immune response inside tumor microenvironment.
However, recent phase I trial of CDN analogs, MK-1454 by Merck, patients showed limited antitumor response.

Moreover, recent findings indicate that there are complex negative feedback mechanisms that restrict the activity,
or reduce the expression of STING. In this study, we demonstrated new strategy that could reverse the recurrent

loss STING for efficient cancer immunotherapy. We discovered novel small molecule that inhibits the interaction
between STING and ubiquitin E3 ligase, thereby blocking the degradation of STING. Upon co-treatment with CDN,

our small molecule augmented cytokine expression. From our findings, we anticipate that our strategy with new
small molecule could enable efficient and enhanced CDN cancer immunotherapy.