SAR study of a novel triene-ansamycin group compound, quinotrierixin, and related compounds, as inhibitors of ER stress-induced XBP1 activation.
In the course of screening for an inhibitor of ER stress-induced XBP1 activation, we isolated a new member of the triene-ansamycin group compound, quinotrierixin, from a culture broth of Streptomyces sp. PAE37. Quinotrierixin inhibited thapsigargin-induced XBP1 activation in HeLa cells with an IC50 of 0.067 microM. We found that other triene-ansamycin group compounds such as demethyltrienomycin A and mycotrienin I also inhibited ER stress-induced XBP1 activation. Moreover, we performed SAR study of twelve triene-ansamycin group compounds. The study showed that OH group at C-13 was crucial, and CH3 group at C-14 would be important for the XBP1 inhibitory activity.
Kawamura
Tatsuro
T
Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
Tashiro
Etsu
E
Yamamoto
Kohta
K
Shindo
Kazutoshi
K
Imoto
Masaya
M
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D013302:Streptomyces / Q000145:classification / Q000302:isolation & purification / Q000378:metabolism*; D013312:Stress, Physiological / Q000378:metabolism; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles; D014157:Transcription Factors / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
D000900:Anti-Bacterial Agents; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D013778:Tetrazolium Salts; D013844:Thiazoles; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C532275:quinotrierixin; D017828:Rifabutin; D008156:Luciferases; C022616:thiazolyl blue