A novel inhibitor of farnesyltransferase with a zinc site recognition moiety and a farnesyl group

[Display omitted] Protein prenylation such as farnesylation and geranylgeranylation is associated with various diseases. Thus, many inhibitors of prenyltransferase have been developed. We report novel inhibitors of farnesyltransferase with a zinc-site recognition moiety and a farnesyl/dodecyl group....

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Published in:Bioorganic & medicinal chemistry letters 2017-08, Vol.27 (16), p.3862-3866
Main Authors: Tanaka, Ayumi, Radwan, Mohamed O., Hamasaki, Akiyuki, Ejima, Asumi, Obata, Emiko, Koga, Ryoko, Tateishi, Hiroshi, Okamoto, Yoshinari, Fujita, Mikako, Nakao, Mitsuyoshi, Umezawa, Kazuo, Tamanoi, Fuyuhiko, Otsuka, Masami
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Cell Proliferation - drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Farnesyl group
Farnesyltransferase
Farnesyltranstransferase - antagonists & inhibitors
Farnesyltranstransferase - metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Organometallic Compounds - chemical synthesis
Organometallic Compounds - chemistry
Organometallic Compounds - pharmacology
Ras protein
Structure-Activity Relationship
Zinc - chemistry
Zinc - pharmacology
Zinc protein
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Summary:[Display omitted] Protein prenylation such as farnesylation and geranylgeranylation is associated with various diseases. Thus, many inhibitors of prenyltransferase have been developed. We report novel inhibitors of farnesyltransferase with a zinc-site recognition moiety and a farnesyl/dodecyl group. Molecular docking analysis showed that both parts of the inhibitor fit well into the catalytic domain of farnesyltransferase. The synthesized inhibitors showed activity against farnesyltransferase in vitro and inhibited proliferation of the pancreatic cell line AsPC-1. Among the compounds with farnesyl and dodecyl groups, the inhibitor with a farnesyl group was found to have stronger and more selective activity.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.06.047