The patent badge is an abbreviated version of the USPTO patent document. The patent badge does contain a link to the full patent document.
The patent badge is an abbreviated version of the USPTO patent document. The patent badge covers the following: Patent number, Date patent was issued, Date patent was filed, Title of the patent, Applicant, Inventor, Assignee, Attorney firm, Primary examiner, Assistant examiner, CPCs, and Abstract. The patent badge does contain a link to the full patent document (in Adobe Acrobat format, aka pdf). To download or print any patent click here.
Patent No.:
Date of Patent:
Sep. 04, 2001
Filed:
Dec. 15, 1999
Hans Peter Spielmann, Lexington, KY (US);
Douglas A. Andres, Lexington, KY (US);
Kareem A. H. Chehade, Lexington, KY (US);
University of Kentucky Research Foundation, Lexington, KY (US);
Abstract
The post-translational addition of a farnesyl moiety to the Ras oncoprotein is essential for its membrane localization and is required for both its biological activity and ability to induce malignant transformation. The present invention describes design and synthesis of a farnesylpyrophosphate (FPP) analog, 8-anilinogeranyl pyrophosphate (AGPP) that is transferred to Ras by farnesyltransferase (FTase), in which the &ohgr;-terminal isoprene unit of the farnesyl group has been replaced with an aniline functionality. AGPP potently inhibited FTase activity in vitro (IC,=0.6 &mgr;M) and is highly selective showing little inhibitory activity against either geranylgeranyl-protein transferase type I (GGTase I) (IC,=31 &mgr;M) or the utilization of FPP by the enzyme squalene synthase (IC,=1000 &mgr;M). Kinetic analyses suggest that AGPP acts as a competitive inhibitor of FTase with respect to FPP. In vitro studies using [,H]AGPP show that the analog was appropriately transferred by FTase to Ras. Derivitization of AGPP with a bulky iodo group on the aniline ring does not significantly alter its biochemical properties. These data indicate that the modified molecules are the first truly transferable analogs of FPP and open the door to additional analogs to probe the biological function of protein farnesylation.