Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I.
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.
Lobell
Robert B
RB
Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. rob_lobell@merck.com
Liu
Dongming
D
Buser
Carolyn A
CA
Davide
Joseph P
JP
DePuy
Elizabeth
E
Hamilton
Kelly
K
Koblan
Kenneth S
KS
Lee
Yih
Y
Mosser
Scott
S
Motzel
Sherri L
SL
Abbruzzese
James L
JL
Fuchs
Charles S
CS
Rowinsky
Eric K
EK
Rubin
Eric H
EH
Sharma
Sunil
S
Deutsch
Paul J
PJ
Mazina
Kathryn E
KE
Morrison
Briggs W
BW
Wildonger
Lynne
L
Yao
Siu-Long
SL
Kohl
Nancy E
NE
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
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