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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 McGovern^1*

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.

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* 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.

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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.

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