CP-609754

CP-609754 (LNK-754) is a potent and reversible farnesyltransferase inhibitor with potential anticancer activity.The IC₅₀ for inhibiting farnesylation of recombinant human H-Ras is 0.57 ng/mL and recombinant K-Ras is 46 ng/mL^[1]. CP-609754 is a click chemistry reagent, itcontains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups. In Vitro: CP-609754 (CP-609,754) is a reversible inhibitor of farnesyltransferase with a slow on/off rate. CP-609,754 inhibits farnesylation (IC₅₀=1.72 ng/mL) of mutant H-Ras in 3T3 H-ras (61L)-transfected cell lines with SDS-PAGE analysis of [³⁵S]methionine-labeled material^[1].
CP-609754 is competitive for the prenyl acceptor (H-Ras protein) and noncompetitive for the prenyl donor farnesyl PPI. CP-609754 interacts with the farnesyltransferase-farnesyl PPI complex and competes for the binding of the Ras protein. CP-609754 selectively inhibits farnesylation of both H- and K-Ras proteins in 3T3 transfectants^[1]. In Vivo: CP-609754 (CP-609,754) has antitumor activity against 3T3 H-ras (61L) tumors in vivo^[1].
With twice daily oral dosing of CP-609754, tumor regression is achieved with a dose of 100 mg/kg; the ED₅₀ for tumor growth inhibition is 28 mg/kg^[1].
With continuous i.p. infusion of CP-609754, tumor growth is inhibited by >50%, and tumor farnesyltransferase activity inhibited by >30% in mice in which the plasma concentration of CP-609754 is maintained above 118 ng/mL^[1].