Preclinical and Clinical Pharmacodynamic Assessment of L-778,123, a Dual Inhibitor of Farnesyl:Protein Transferase and Geranylgeranyl:Protein Transferase Type-I

• Published in: Molecular cancer therapeutics 2002-07, Vol.1 (9), p.747-758
• Main Authors: Lobell, Robert B, Liu, Dongming, Buser, Carolyn A, Davide, Joseph P, DePuy, Elizabeth, Hamilton, Kelly, Koblan, Kenneth S, Lee, Yih, Mosser, Scott, Motzel, Sherri L, Abbruzzese, James L, Fuchs, Charles S, Rowinsky, Eric K, Rubin, Eric H, Sharma, Sunil, Deutsch, Paul J, Mazina, Kathryn E, Morrison, Briggs W, Wildonger, Lynne, Yao, Siu-Long, Kohl, Nancy E
• Format: Article
• Language: English
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Animals; Antineoplastic Agents - pharmacology; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Humans; Imidazoles - pharmacology; Immunoblotting; Leukocytes - drug effects; Leukocytes, Mononuclear - drug effects; Mice; Models, Chemical; Proto-Oncogene Proteins p21(ras) - metabolism; rap1 GTP-Binding Proteins - metabolism; Time Factors
• ISSN: 1535-7163; 1538-8514

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.