Anticancer agents based on regulation of protein prenylation

US7019031B2 · kind B2 · utility

Assignee

• The Arizona Disease Control Research Commission · US

Inventors

• Seth D. Rose · Tempe, US
• Scott Lefler · Tempe, US
• Steven R. Ottersberg · Tempe, US
• Ann Kim · Glendale, US
• Karl J. Okolotowicz · Tempe, US
• Rosemarie F. Hartman · Springdale, US

Key dates

• Filing date: Oct 23, 2001
• Grant date: Mar 28, 2006
• Expiry date: Feb 6, 2023

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07F9/091
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

Oncoproteins such as Ras and RhoB are known to induce cell division in an unrestrained manner when such proteins are localized at the inner surface of a cancer cell membrane. The localization is effected by the prenylation reaction, whereby a hydrophobic group (e.g. a farnesyl group) is attached to the protein in the presence of an enzyme (e.g. farnesyl protein transferase). Deactivation of the prenylation enzyme through covalent modification can therefore ultimately result in the mitigation and/or cessation of cancer cell growth. Various prenylation inhibitors having the necessary structural groups to bond covalently, or essentially irreversibly, to the prenylation enzyme include carbonyl or thiocarbonyl compounds (or masked versions of these compounds) and alpha oxo-epoxides bonded to a hydrophobic, substrate-mimicking group. The carbonyl or thiocarbonyl compounds also contain a nucleofugal atom or group to enhance the tendency to form covalent bonds.