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초록

The cGAS-STING signaling pathway is an essential mechanism in the recruitment and activation of innate and adaptive immune cells to exert an antitumor response in cancer immunotherapy. cGAMP is a crucial immunotransmitter, which is potentially degraded by ENPP1, resulting in the deactivation of STING-mediated antitumor immune responses. We herein describe the design, synthesis, and biological evaluation of novel ENPP1 inhibitors containing a benzotriazole core and a sulfonimidamide Zn binder. Notably, compound 44a demonstrated potent and selective ENPP1 inhibition with an IC50 value of 13.1 nM and effectively activated the STING pathway in HCT116-Dual™ cells. Additionally, compound 44a exhibited a notable release of cytokines in THP-1 cell lines, thereby enhancing the innate immune response. The oral administration of compound 44a displayed remarkable antitumor efficacy in the MC38 syngeneic mouse model without notable toxicity. Therefore, compound 44a can be considered a promising candidate as a selective and orally bioavailable ENPP1 inhibitor.

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