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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 1/2011

01-01-2011 | Original Article

Characterization of the in vitro activity of AZD3409, a novel prenyl transferase inhibitor

Authors: Natalie M. G. M. Appels, Maria J. Bolijn, Maria A. J. van Eijndhoven, Trevor C. Stephens, Jos H. Beijnen, Jan H. M. Schellens

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2011

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Abstract

Purpose

AZD3409 is a novel DPTI that has potent activity against both FTase and GGTase-1. The in vitro inhibition profile of AZD3409 was characterized using three different cell lines: mouse embryogenic fibroblasts, transfected with H-RasV12 (MEF), A549 cells (Ki4B-Ras mutation) and MCF-7 cells (no Ras mutation).

Methods

Both cytotoxicity and levels of inhibition of farnesylation and geranylgeranylation were determined in different assays in relation to the concentration of AZD3409. Results were compared with those obtained with the first-generation FTase inhibitor lonafarnib or the GGTase-1 inhibitor GGTI-2147.

Results

The mean IC50 for cytotoxicity of AZD3409 and lonafarnib was 510 and 15,200 nM in MEF cells, 10,600 and 2,740 nM in A549 cells and 6,170 and 9,490 nM in MCF7 cells, respectively. In these cells, the IC50 for FTase activity of AZD3409 ranged from 3.0 to 14.2 nM and of lonafarnib from 0.26 to 31.3 nM. The inhibiting activity of AZD3409 and lonafarnib on general protein farnesylation was comparable with the specific farnesylation levels of HDJ-2. In vitro geranylgeranylation of Rap1a could be inhibited by GGTI-2147 in all three cell lines, but only in MCF-7 cells by AZD3409. These results are in agreement with the IC50 values for GGTase-1 activity as the lowest IC50 for AZD3409 was found in the MCF-7 cell line.

Conclusions

AZD3409 inhibits farnesylation to a higher extent than geranylgeranylation. Both inhibition of farnesylation and geranylgeranylation could not be correlated to the antiproliferative activity of the drug.
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Metadata
Title
Characterization of the in vitro activity of AZD3409, a novel prenyl transferase inhibitor
Authors
Natalie M. G. M. Appels
Maria J. Bolijn
Maria A. J. van Eijndhoven
Trevor C. Stephens
Jos H. Beijnen
Jan H. M. Schellens
Publication date
01-01-2011
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 1/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-010-1300-6

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