Novel chemical compound SINCRO with dual function in STING‐type I interferon and tumor cell death pathways. Issue 9 (1st August 2018)

• Record Type: Journal Article
• Authors: Kimura, Yoshitaka; Negishi, Hideo; Matsuda, Atsushi; Endo, Nobuyasu; Hangai, Sho; Inoue, Asuka; Nishio, Junko; Taniguchi, Tadatsugu; Yanai, Hideyuki
• Is Part Of: Cancer science. Volume 109:Issue 9(2018)
• Page Start: 2687
• Page End: 2696
• Publication Date: 2018-08-01
• Subjects: anticancer drug -- cancer immunity -- cytotoxicity -- STING -- type I interferon; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.13726
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract : Recent years have seen a number of regulatory approvals for immune oncology or immunotherapies based on their ability to enhance antitumor immune responses. Nevertheless, the majority of patients remain refractory to these treatments; hence, new therapies that augment current immunotherapies are required. Innate immune receptors that recognize nucleic acids are potent activators of subsequent T‐cell responses and, as a result, can evoke potent antitumor immune responses. Herein, 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 anticancer 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 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 method different from conventional apoptosis‐inducing pathways. Finally, we provide evidence that giving SINCRO significantly attenuates in vivo tumor growth by both type I IFN‐dependent and independent mechanisms. Thus, SINCRO is an attractive anticancer compound with dual function in that it evokes type I IFN response to promote antitumor immunity as well as inducing tumor cell death. SINCRO may provide a new platform for the development of drugs for effective cancer therapy. Abstract : We find 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 a novel anticancer compound. SINCRO induces type I interferon gene expression through STING and exerts cytotoxic activity against cancer cells in a STING‐independent method. Thus, SINCRO is an attractive compound with dual anticancer function.