Novel chemical compound SINCRO with dual function in STING-type I interferon and tumor cell death pathways

Yoshitaka Kimura, Hideo Negishi, Atsushi Matsuda, Nobuyasu Endo, Sho Hangai, Asuka Inoue, Junko Nishio, Tadatsugu Taniguchi, Hideyuki Yanai

研究成果: Article査読

7 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)2687-2696
ページ数10
ジャーナルCancer science
109
9
DOI
出版ステータスPublished - 2018 9月
外部発表はい

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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