RRC ID 55965
Author Kimura Y, Negishi H, Matsuda A, Endo N, Hangai S, Inoue A, Nishio J, Taniguchi T, Yanai H.
Title Novel chemical compound SINCRO with dual function in STING-type I interferon and tumor cell death pathways.
Journal Cancer Sci
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.
Volume 109(9)
Pages 2687-2696
Published 2018-9
DOI 10.1111/cas.13726
PMID 29981256
PMC PMC6125434
MeSH 3T3 Cells Amides / chemistry Amides / pharmacology* Animals Antineoplastic Agents / pharmacology* Apoptosis / drug effects* Cell Line, Tumor Cell Proliferation / drug effects DNA Breaks, Double-Stranded / drug effects HEK293 Cells HeLa Cells Humans Immunity, Innate / drug effects* Interferon-beta / biosynthesis* Interferon-beta / genetics Interferon-beta / metabolism Membrane Proteins / metabolism* Mice Mice, Inbred C57BL Mice, Knockout Neoplasms / drug therapy* Neoplasms / immunology* Neoplasms / pathology Picolinic Acids / chemistry Picolinic Acids / pharmacology* Piperidines / chemistry Piperidines / pharmacology* Signal Transduction / drug effects
IF 4.751
Times Cited 2
Resource
Human and Animal Cells EL4(RCB1641)