Cancer science 2018 07 07() doi 10.1111/cas.13726

Abstract

Recent years have seen a number of regulatory approvals for immune oncology or immunotherapies based on their ability to enhance anti-tumor immune responses. Nevertheless, the majority of the patients remain refractory to these treatments; hence, new therapies that augment current immunotherapies are required. Innate immune receptors that recognize nucleic acid are potent activators of subsequent T cell responses and, as a result, can evoke potent anti-tumor immune responses. Here, we present a novel compound N-{3-[(1,4′-bipiperidin)-1′-yl]propyl}-6-[4-(4-methylpiperazin-1-yl)phenyl]picolinamide (SINCRO; STING-mediated interferon-inducing and cytotoxic reagent, original) as an anti-cancer drug that activates the cytosolic DNA-sensing STING (stimulator of interferon genes) signaling pathway leading to the induction of type I interferon (IFN) genes. Indeed, IFN-β gene induction by SINCRO is abolished in STING-deficient cells. In addition to its IFN-inducing activity, SINCRO shows a STING-independent cytotoxic activity against cancer cells. SINCRO does not evoke DNA double-strand break or caspase-3 cleavage. Thus, SINCRO induces cell death in a manner different from conventional apoptosis-inducing pathways. Finally, we provide evidence that SINCRO administration significantly attenuates in vivo tumor growth by both type I IFN-dependent and independent mechanisms. Thus, SINCRO is an attractive anti-cancer compound with dual function in that it evokes type I IFN response to promote anti-tumor immunity on the one hand and induces tumor cell death on the other hand. SINCRO may provide a new platform for the development of drugs for effective cancer therapy. This article is protected by copyright. All rights reserved.