1.Arylsulfonamide KCN1 inhibits in vivo glioma growth and interferes with HIF signaling by disrupting HIF-1α interaction with cofactors p300/CBP.
Yin S1, Kaluz S, Devi NS, Jabbar AA, de Noronha RG, Mun J, Zhang Z, Boreddy PR, Wang W, Wang Z, Abbruscato T, Chen Z, Olson JJ, Zhang R, Goodman MM, Nicolaou KC, Van Meir EG. Clin Cancer Res. 2012 Dec 15;18(24):6623-33. doi: 10.1158/1078-0432.CCR-12-0861. Epub 2012 Aug 24.
PURPOSE: The hypoxia-inducible factor-1 (HIF-1) plays a critical role in tumor adaptation to hypoxia, and its elevated expression correlates with poor prognosis and treatment failure in patients with cancer. In this study, we determined whether 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1, the lead inhibitor in a novel class of arylsulfonamide inhibitors of the HIF-1 pathway, had antitumorigenic properties in vivo and further defined its mechanism of action.
2.Genomic structure and regulation of Kcn1, a cGMP-gated potassium channel.
Yao X1, Liu Y, Tung F, Desir GV. Am J Physiol. 1996 Jul;271(1 Pt 2):F37-41.
We recently cloned a novel rabbit gene that encodes a 725-amino acid protein (Kcn1) (Y. Yao, A. S. Segal, P. Welling, X. Zhang, C. M. McNicholas, D. Engel, E. L. Boulpaep, and G. Desir. Proc. Natl. Acad. Sci. USA 92: 11711-11715, 1995). Kcn1 RNA injected in Xenopus oocytes leads to the expression of potassium channels that are specifically activated by guanosine 3',5'-cyclic monophosphate (cGMP). Northern blot and ribonuclease (RNase) protection analysis show that Kcn1 is differentially expressed in kidney, aorta, brain, and heart. The purpose of present study is to determine the structure of Kcn1 gene, analyze the promoter region, and identify cis-regulatory elements responsible for transcription. We find that the coding region of Kcn is intronless. The major transcription initiation site was identified by primer extension. Sequence analysis of the 5'-flanking region indicates that, although the gene lacks a typical TATA box, it does have a TATA-box-like region (-TAT-).
3.KCN1, a novel synthetic sulfonamide anticancer agent: in vitro and in vivo anti-pancreatic cancer activities and preclinical pharmacology.
Wang W1, Ao L, Rayburn ER, Xu H, Zhang X, Zhang X, Nag SA, Wu X, Wang MH, Wang H, Van Meir EG, Zhang R. PLoS One. 2012;7(9):e44883. doi: 10.1371/journal.pone.0044883. Epub 2012 Sep 13.
The purpose of the present study was to determine the in vitro and in vivo anti-cancer activity and pharmacological properties of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1. In the present study, we investigated the in vitro activity of KCN1 on cell proliferation and cell cycle distribution of pancreatic cancer cells, using the MTT and BrdUrd assays, and flow cytometry. The in vivo anti-cancer effects of KCN1 were evaluated in two distinct xenograft models of pancreatic cancer. We also developed an HPLC method for the quantitation of the compound, and examined its stability in mouse plasma, plasma protein binding, and degradation by mouse S9 microsomal enzymes. Furthermore, we examined the pharmacokinetics of KCN1 following intravenous or intraperitoneal injection in mice. Results showed that, in a dose-dependent manner, KCN1 inhibited cell growth and induced cell cycle arrest in human pancreatic cancer cells in vitro, and showed in vivo anticancer efficacy in mice bearing Panc-1 or Mia Paca-2 tumor xenografts.