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J. Biol. Chem., Vol. 283, Issue 15, 9571-9579, April 11, 2008

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Inhibitors of Protein Geranylgeranyltransferase I and Rab Geranylgeranyltransferase Identified from a Library of Allenoate-derived Compounds^*

Masaru Watanabe, Hannah D. G. Fiji, Lea Guo, Lai Chan^¶, Sape S. Kinderman, Dennis J. Slamon^||, Ohyun Kwon, and Fuyuhiko Tamanoi¹

From the Microbiology, Immunology, and Molecular Genetics and Chemistry and Biochemistry, the ^¶Molecular Biology Institute, and the ^||Department of Medicine, Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095

Protein geranylgeranylation is critical for the function of a number of proteins such as RhoA, Rac, and Rab. Protein geranylgeranyltransferase I (GGTase-I) and Rab geranylgeranyltransferase (RabGGTase) catalyze these modifications. In this work, we first describe the identification and characterization of small molecule inhibitors of GGTase-I (GGTI) with two novel scaffolds from a library consisting of allenoate-derived compounds. These compounds exhibit specific inhibition of GGTase-I and act by competing with a substrate protein. Derivatization of a carboxylic acid emanating from the core ring of one of the GGTI compounds dramatically improves their cellular activity. The improved GGTI compounds inhibit proliferation of a variety of human cancer cell lines and cause G₁ cell cycle arrest and induction of p21^CIP1/WAF1. We also report the identification of novel small molecule inhibitors of RabGGTase. These compounds were identified first by screening our GGTI compounds for those that also exhibited RabGGTase inhibition. This led to the discovery of a common structural feature for RabGGTase inhibitors: the presence of a characteristic six-atom aliphatic tail attached to the penta-substituted pyrrolidine core. Further screening led to the identification of compounds with preferential inhibition of RabGGTase. These compounds inhibit RabGGTase activity by competing with the substrate protein. These novel compounds may provide valuable reagents to study protein geranylgeranylation.

Received for publication, July 30, 2007 , and in revised form, January 28, 2008.

^* This work was supported by National Institutes of Health Grants CA32737 (to F. T.) and GM071779 (to O. K.) and by a grant from the Susan E. Riley Foundation. The flow cytometric analysis done in the UCLA Flow Cytometry Core Facilities was supported in part by National Institutes of Health Grants CA16042 and AI28697. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and Tables S1 and S2.

¹ To whom correspondence should be addressed: Dept of Microbiology, Immunology, and Molecular Genetics, UCLA, 1602 Molecular Sciences Bldg., 609 Charles E. Young Dr., Los Angeles, CA 90095. Fax: 310-206-7318; E-mail: fuyut{at}microbio.ucla.edu.

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