M335, a novel small-molecule STING agonist activates the immune response and exerts antitumor effects.

In the context of antitumor immune responses, the activation of the stimulator of interferon genes (STING) assumes a critical role and imparts enhanced immunogenicity. An effective strategy for exogenously activating the immune system involves the utilization of STING agonists, and prior investigations primarily concentrated on modifying endogenous cyclic dinucleotides (CDNs) to achieve this. Nevertheless, the practical utility of CDNs was restricted due to limitations associated with their physicochemical attributes and administration protocols. In this article, we present the discovery of a novel small-molecule agonist denoted as M335, identified through high-throughput screening using surface plasmon resonance (SPR). M335 demonstrates the ability to activate the TBK1-IRF3-IFN axis in a STING-dependent manner in vitro. Through experimentation on mouse models bearing tumors, we observed that the administration of M335 resulted in the activation of immune cells. Notably, significant antitumor effects were achieved with both intratumoral and intraperitoneal administration of M335. These findings suggest the potential of M335 as a promising agent for cancer immunotherapy, which will promote the development of STING agonists in anti-tumor applications. A novel small-molecule STING agonist M335 was identified, and the growth of cold tumors were significantly inhibited as the activation of immunity after administration of M335 either intratumorally or intraperitoneally. [Display omitted] •A novel small-molecular STING agonist M335 was identified. •M335 targets STING with weak interaction to active immune pathway. •The alkylamine moiety of M335 is crucial for the activity. •M335 exerts antitumor effect in vivo by activating immune cells. •M335 was effective both intratumoral and intraperitoneal administration. [ABSTRACT FROM AUTHOR]