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The activation of stimulator of interferon genes (STING) signaling pathways plays an important role in the innate immune response. Although several STING agonists have been developed recently, the majority of clinical CDN STING agonists are administered by intratumoral (IT) injection. Therefore, there remains a need to develop diverse non-CDN small-molecule STING agonists with systemic administration. Herein, by using a scaffold hopping strategy, we designed a series of thieno [2,3-d]imidazole derivatives as novel STING agonists. Further structure-activity relationship study and optimization led to the discovery of compound 45 as a highly potent human STING agonist with an EC

Pharmacological activation of stimulator of interferon genes (STING) by agonists has emerged as a new modality of cancer immunotherapy. However, current available STING agonists remain in early developmental stage or failed in clinic trials due to limited efficacy in humans. In this report, we performed a structure-activity relationship study based on the benzothiophene oxobutanoic acid scaffold of MSA-2, a well-documented STING agonist by Merck, leading to a series of N-substituted acyloxyamino derivatives with potent STING activating effect. Among them, compounds 57 and 60 displayed the most potent activity specifically targeting both h- and m-STING. Particularly, 57 displayed more potent and rapid activation of the STING signaling pathway than ADU-S100 in THP1-Dual cells. In vivo anti-tumor efficacy of 57 by intratumoral or oral administration was also demonstrated in several mouse tumor models. Intriguingly, treatment with 57 eradicated all the CT26 tumor without further recurrence in all treated mice, which could also reject the same tumor re-inoculation, indicating an induction of immune memory by 57. Taken together, acyloxyamino derivative 57 represents a new chemotype of STING agonist with well-demonstrated in vivo anti-tumor activity, which is deserved for further investigation.

Ceramides have emerged as potential therapeutic option with novel mechanism to affect the proliferation, differentiation, senescence, and apoptosis of cancer cells through regulation of multiple signal transduction. Aiming at the improvement of the apoptosis activity and pharmacokinetic profiles of ceramides, a novel series of ceramide analogs were developed through structure simplification and conformation restriction. Among them, compound 12 bearing an alkoxyl naphthyl motif, with favorable rat pharmacokinetic properties, showed better anti-proliferative activity against various colon cancer cells (IC50 ∼20 μM) than other ceramide analogues, as well as the synergistic effect combined with AKT inhibitor MK2206. Additionally, we demonstrated that this combination therapy promoted caspase 3-dependent apoptotic pathway and intensified cell cycle arrest in the G0/G1 phase. Furthermore, the combination of compound 12 and MK2206 displayed synergistic anti-tumor effect in vivo.