Abstract
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 μM. 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.
Similar content being viewed by others
Article PDF
References
Ron D, Walter P . Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8: 519–529 ( 2007)
Moenner M, Pluquet O, Bouchecareilh M, Chevet E . Integrated endoplasmic reticulum stress responses in cancer. Cancer Res 67: 10631–10634 ( 2007)
Romero-Ramirez L, Cao H, Nelson D, Hammond E, Lee AH, Yoshida H, Mori K, Glimcher LH, Denko NC, Giaccia AJ, Le QT, Koong AC . XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res 64: 5943–5947 ( 2004)
Fujimoto T, Onda M, Nagai H, Nagahata T, Ogawa K, Emi M . Upregulation and overexpression of human X-box binding protein 1 (hXBP-1) gene in primary breast cancers. Breast Cancer 10: 301–306 ( 2003)
Shuda M, Kondoh N, Imazeki N, Tanaka K, Okada T, Mori K, Hada A, Arai M, Wakatsuki T, Matsubara O, Yamamoto N, Yamamoto M . Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 38: 605–614 ( 2003)
Tashiro E, Hironiwa N, Kitagawa M, Futamura Y, Suzuki S, Nishio M, Imoto M . Trierixin, a novel inhibitor of ER stress-induced XBP1 activation from Streptomyces sp. I. Taxonomy, fermentation, isolation and biological activities. J Antibiot 60: 547–553 ( 2007)
Kawamura T, Tashiro E, Shindo K, Imoto M . SAR study of a novel triene-ansamycin group compound, quinotrierixin, and related compounds, as inhibitors of ER stress-induced XBP1 activation. II. Structure elucidation. J Antibiot 61: 312–317 ( 2008)
Sugita M, Natori Y, Sasaki T, Furihata K, Shimazu A, Seto H, Otake N . Studies on mycotrienin antibiotics, a novel class of ansamycins. I. Taxonomy, fermentation, isolation and properties of mycotrienins I and II. J Antibiot 35: 1460–1466 ( 1982)
Umezawa I, Funayama S, Okada K, Iwasaki K, Satoh J, Masuda K, Komiyama K . Studies on a novel cytocidal antibiotic, trienomycin A. Taxonomy, fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot 38: 699–705 ( 1985)
Sugita M, Natori Y, Sueda N, Furihata K, Seto H, Otake N . Studies on mycotrienin antibiotics, a novel class of ansamycins. III. The isolation, characterization and structures of mycotrienols I and II. J Antibiot 35: 1474–1479 ( 1982)
Kim WG, Song NK, Yoo ID . Trienomycin G, a new inhibitor of nitric oxide production in microglia cells, from Streptomyces sp. 91614. J Antibiot 55: 204–207 ( 2002)
Feuerbach D, Waelchli R, Fehr T, Feyen JH . Mycotrienins. A new class of potent inhibitors of osteoclastic bone resorption. J Biol Chem 270: 25949–25955 ( 1995)
Funayama S, Anraku Y, Mita A, Yang ZB, Shibata K, Komiyama K, Umezawa I, Omura S . Structure-activity relationship of a novel antitumor ansamycin antibiotic trienomycin A and related compounds. J Antibiot 41: 1223–1230 ( 1988)
Watabe M, Kakeya H, Onose R, Osada H . Activation of MST/Krs and c-Jun N-terminal kinases by different signaling pathways during cytotrienin A-induced apoptosis. J Biol Chem 275: 8766–8771 ( 2000)
Nishio M, Kohno J, Sakurai M, Suzuki SI, Okada N, Kawano K, Komatsubara S . TMC-135A and B, new triene-ansamycins, produced by Streptomyces sp. J Antibiot 53: 724–727 ( 2000)
Hosokawa N, Naganawa H, Iinuma H, Hamada M, Takeuchi T, Kanbe T, Hori M . Thiazinotrienomycins, new ansamycin group antibiotics. J Antibiot 48: 471–478 ( 1995)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kawamura, T., Tashiro, E., Yamamoto, K. et al. SAR Study of a Novel Triene-ansamycin Group Compound, Quinotrierixin, and Related Compounds, as Inhibitors of ER Stress-induced XBP1 Activation. J Antibiot 61, 303–311 (2008). https://doi.org/10.1038/ja.2008.43
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ja.2008.43
Keywords
This article is cited by
-
Screening and identification of inhibitors of endoplasmic reticulum stress-induced activation of the IRE1α-XBP1 branch
The Journal of Antibiotics (2019)
-
PK/PD analysis of biapenem in patients undergoing continuous hemodiafiltration
Journal of Pharmaceutical Health Care and Sciences (2015)
-
New ansamycin analogues from the mutant strain of Streptomyces seoulensis
The Journal of Antibiotics (2015)
-
Optimal dosing of antibiotics in critically ill patients by using continuous/extended infusions: a systematic review and meta-analysis
Critical Care (2013)
-
Targeting the unfolded protein response in disease
Nature Reviews Drug Discovery (2013)