title: Identification of novel kynurenine production-inhibiting benzenesulfonamide derivatives in cancer cells.
abstract: Kynurenine (Kyn), a metabolite of tryptophan (Trp), is known to be a key regulator of human immune responses including cancer immune tolerance. Therefore, abrogation of Kyn production from cancer cells by small molecules may be a promising approach to anticancer therapy. Indeed, several small molecule inhibitors of indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme in the catabolism of Trp to Kyn, exert antitumor effects in animal models. We screened our chemical libraries using a cell-based Kyn production assay to identify a new type of small molecules that regulate Kyn production, and for the first time identified a benzenesulfonamide derivative (compound 1) as a hit with the ability to inhibit Kyn production in interferon-γ (IFN-γ)-stimulated A431 and HeLa cells. Unlike the previously identified S-benzylisothiourea derivative, compound 2, compound 1 had little effect on the enzymatic activity of recombinant human IDO in vitro but suppressed the expression of IDO at the mRNA level in cells. Furthermore, compound 1 suppressed STAT1-dependent transcriptional activity and DNA binding, whereas no decrement in either the expression or phosphorylation level of STAT1 was observed. The inhibition of IDO expression by several benzenesulfonamide derivatives is associated with the suppression of STAT1. Thus, compound 1 and its analogs might be useful for analyzing the regulation of IDO activation, and STAT1-targeting could be an alternative to the IDO-directed approach for the regulation of Kyn levels by small molecules in the tumor microenvironment.
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nakano
authors.forename: Kazushige
authors.initials: K
authors.lastname: Takai
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Isaka
authors.forename: Susumu
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Unno
authors.forename: Naohisa
authors.initials: N
authors.lastname: Ogo
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuno
authors.forename: Osamu
authors.initials: O
authors.lastname: Takikawa
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D007737:Kynurenine / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors; D054852:Small Molecule Libraries; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D050794:STAT1 Transcription Factor; D054852:Small Molecule Libraries; D013449:Sulfonamides; D000096926:Benzenesulfonamides