title: Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I.
abstract: Farnesyl:protein transferase (FPTase) inhibitors were developed as anti-Ras drugs, but they fail to inhibit Ki-Ras activity because Ki-Ras can be modified by geranylgeranyl:protein transferase type-I (GGPTase-I). L-778,123, an inhibitor of FPTase and GGPTase-I, was developed in part because it can completely inhibit Ki-Ras prenylation. To support the clinical development of L-778,123, we developed pharmacodynamic assays using peripheral blood mononuclear cells (PBMCs) to measure the inhibition of prenylation of HDJ2 and Rap1A, proteins that are FPTase- and GGPTase-I substrates, respectively. We validated these assays in animal models and show that inhibition of HDJ2 prenylation in mouse PBMCs correlates with the concentration of FPTase inhibitors in blood. In dogs, continuous infusion of L-778,123 inhibited both HDJ2 and Rap1A prenylation in PBMCs, but we did not detect inhibition of Ki-Ras prenylation. We reported previously results from the first L-778,123 Phase I trial that showed a dose-dependent inhibition of HDJ2 farnesylation in PBMCs. In this report, we present additional analysis of patient samples from this trial and a second Phase I trial of L-778,123, and demonstrate the inhibition of both HDJ2 and Rap1A prenylation in PBMC samples. This study represents the first demonstration of GGPTase-I inhibition in humans. However, no inhibition of Ki-Ras prenylation by L-778,123 was detected in patient samples. These results confirm the pharmacologic profile of L-778,123 in humans as a dual inhibitor of FPTase and GGPTase-I, but indicate that the intended target of the drug, Ki-Ras, was not inhibited.
authors.affiliation: Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. rob_lobell@merck.com
authors.forename: Robert B
authors.initials: RB
authors.lastname: Lobell
authors.forename: Dongming
authors.initials: D
authors.lastname: Liu
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Davide
authors.forename: Elizabeth
authors.initials: E
authors.lastname: DePuy
authors.forename: Kelly
authors.initials: K
authors.lastname: Hamilton
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Koblan
authors.forename: Yih
authors.initials: Y
authors.lastname: Lee
authors.forename: Scott
authors.initials: S
authors.lastname: Mosser
authors.forename: Sherri L
authors.initials: SL
authors.lastname: Motzel
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Eric H
authors.initials: EH
authors.lastname: Rubin
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Deutsch
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Mazina
authors.forename: Briggs W
authors.initials: BW
authors.lastname: Morrison
authors.forename: Lynne
authors.initials: L
authors.lastname: Wildonger
authors.forename: Siu-Long
authors.initials: SL
authors.lastname: Yao
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015151:Immunoblotting; D007962:Leukocytes / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D051379:Mice; D008956:Models, Chemical; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D013997:Time Factors; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; C425231:L 778,123; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020827:rap1 GTP-Binding Proteins