Eukaryotic Cell
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wu, L.
Right arrow Articles by McGovern, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wu, L.
Right arrow Articles by McGovern, K.
Eukaryotic Cell, April 2003, p. 256-264, Vol. 2, No. 2
1535-9778/03/$08.00+0     DOI: 10.1128/EC.2.2.256-264.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Novel Small-Molecule Inhibitors of RNA Polymerase III

Liping Wu,1 Jing Pan,1 Vala Thoroddsen,1 Deborah R. Wysong,1 Ronald K. Blackman,1 Christine E. Bulawa,1 Alexandra E. Gould,1 Timothy D. Ocain,1 Lawrence R. Dick,1 Patrick Errada,1 Patrick K. Dorr,2 Tanya Parkinson,2 Tony Wood,2 Daniel Kornitzer,3 Ziva Weissman,3 Ian M. Willis,4 and Karen McGovern1*

Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts,1 Pfizer Global Research and Development, Sandwich, United Kingdom,2 B. Rappaport Faculty of Medicine, Haifa, Israel,3 Albert Einstein College of Medicine, Bronx, New York4

Received 28 October 2002/ Accepted 15 January 2003

A genetic approach utilizing the yeast Saccharomyces cerevisiae was used to identify the target of antifungal compounds. This analysis led to the identification of small molecule inhibitors of RNA polymerase (Pol) III from Saccharomyces cerevisiae. Three lines of evidence show that UK-118005 inhibits cell growth by targeting RNA Pol III in yeast. First, a dominant mutation in the g domain of Rpo31p, the largest subunit of RNA Pol III, confers resistance to the compound. Second, UK-118005 rapidly inhibits tRNA synthesis in wild-type cells but not in UK-118005 resistant mutants. Third, in biochemical assays, UK-118005 inhibits tRNA gene transcription in vitro by the wild-type but not the mutant Pol III enzyme. By testing analogs of UK-118005 in a template-specific RNA Pol III transcription assay, an inhibitor with significantly higher potency, ML-60218, was identified. Further examination showed that both compounds are broad-spectrum inhibitors, displaying activity against RNA Pol III transcription systems derived from Candida albicans and human cells. The identification of these inhibitors demonstrates that RNA Pol III can be targeted by small synthetic molecules.

* Corresponding author. Mailing address: Infinity Pharmaceuticals, Inc., 780 Memorial Dr., Cambridge, MA 02139. Phone: (617) 453-1173. Fax: (617) 453-1001. E-mail: kmcgovern{at}ipi.com.

Eukaryotic Cell, April 2003, p. 256-264, Vol. 2, No. 2
1535-9778/03/$08.00+0     DOI: 10.1128/EC.2.2.256-264.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:



HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Appl. Environ. Microbiol. Infect. Immun. J. Bacteriol.
Mol. Cell Biol. Microbiol. Mol. Biol. Rev. ALL ASM JOURNALS
Copyright © 2003 by the American Society for Microbiology.