Abstract
AG 879 has been widely used as a Tyr kinase inhibitor specific for ErbB2 and FIK-1, a VEGF receptor. The IC50 for both ErbB2 and FIK-1 is around 1 μM. AG 879, in combination of PP1 (an inhibitor specific for Src kinase family), suppresses almost completely the growth of RAS-induced sarcomas in nude mice. In this paper we demonstrate that AG 879 even at 10 nM blocks the specific interaction between the Tyr-kinase ETK and PAK1 (a CDC42/ Rac-dependent Ser/ Thr kinase) in cell culture. This interaction is essential for both the RAS-induced PAK1 activation and transformation of NIH 3T3 fibroblasts. However, AG 879 at 10 nM does not inhibit either the purified ETK or PAK1 directly in vitro, suggesting that this drug blocks the ETK-PAK1 pathway by targeting a highly sensitive kinase upstream of ETK Although the Tyr-kinases Src and FAK are known to activate ETK directly, Src is insensitive to AG 879, and FAK is inhibited by 100 nM AG 879, but notby 10 nM AG879. The structure-function relationship analysis of AG 879 derivatives has revealed that both thio and tert-butyl groups of AG 879, but not (thio) amide group, are essential for its biological function (blocking the ETK-PAK1 pathway), suggesting that through the (thio) amide group, AG 879 can be covalently linked to agarose beads to form a bioactive affinity ligand useful for identifying the primary target of this drug.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 96-101 |
| Number of pages | 6 |
| Journal | Cancer Biology and Therapy |
| Volume | 3 |
| Issue number | 1 |
| State | Published - Jan 2004 |
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Keywords
- AG879
- ETK
- PAK
- RAS
- Transformation
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation. / He, Hong; Hirokawa, Yumiko; Gazit, Aviv; Yamashita, Yoshihiro; Mano, Hiroyuki; Kawakami, Yuko; Kawakami; Hsieh, Ching Yi; Kung, Hsing-Jien; Lessene, Guillaume; Baell, Jonathan; Levitzki, Alexander; Maruta, Hiroshi.
In: Cancer Biology and Therapy, Vol. 3, No. 1, 01.2004, p. 96-101.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation
AU - He, Hong
AU - Hirokawa, Yumiko
AU - Gazit, Aviv
AU - Yamashita, Yoshihiro
AU - Mano, Hiroyuki
AU - Kawakami, Yuko
AU - Kawakami,
AU - Hsieh, Ching Yi
AU - Kung, Hsing-Jien
AU - Lessene, Guillaume
AU - Baell, Jonathan
AU - Levitzki, Alexander
AU - Maruta, Hiroshi
PY - 2004/1
Y1 - 2004/1
N2 - AG 879 has been widely used as a Tyr kinase inhibitor specific for ErbB2 and FIK-1, a VEGF receptor. The IC50 for both ErbB2 and FIK-1 is around 1 μM. AG 879, in combination of PP1 (an inhibitor specific for Src kinase family), suppresses almost completely the growth of RAS-induced sarcomas in nude mice. In this paper we demonstrate that AG 879 even at 10 nM blocks the specific interaction between the Tyr-kinase ETK and PAK1 (a CDC42/ Rac-dependent Ser/ Thr kinase) in cell culture. This interaction is essential for both the RAS-induced PAK1 activation and transformation of NIH 3T3 fibroblasts. However, AG 879 at 10 nM does not inhibit either the purified ETK or PAK1 directly in vitro, suggesting that this drug blocks the ETK-PAK1 pathway by targeting a highly sensitive kinase upstream of ETK Although the Tyr-kinases Src and FAK are known to activate ETK directly, Src is insensitive to AG 879, and FAK is inhibited by 100 nM AG 879, but notby 10 nM AG879. The structure-function relationship analysis of AG 879 derivatives has revealed that both thio and tert-butyl groups of AG 879, but not (thio) amide group, are essential for its biological function (blocking the ETK-PAK1 pathway), suggesting that through the (thio) amide group, AG 879 can be covalently linked to agarose beads to form a bioactive affinity ligand useful for identifying the primary target of this drug.
AB - AG 879 has been widely used as a Tyr kinase inhibitor specific for ErbB2 and FIK-1, a VEGF receptor. The IC50 for both ErbB2 and FIK-1 is around 1 μM. AG 879, in combination of PP1 (an inhibitor specific for Src kinase family), suppresses almost completely the growth of RAS-induced sarcomas in nude mice. In this paper we demonstrate that AG 879 even at 10 nM blocks the specific interaction between the Tyr-kinase ETK and PAK1 (a CDC42/ Rac-dependent Ser/ Thr kinase) in cell culture. This interaction is essential for both the RAS-induced PAK1 activation and transformation of NIH 3T3 fibroblasts. However, AG 879 at 10 nM does not inhibit either the purified ETK or PAK1 directly in vitro, suggesting that this drug blocks the ETK-PAK1 pathway by targeting a highly sensitive kinase upstream of ETK Although the Tyr-kinases Src and FAK are known to activate ETK directly, Src is insensitive to AG 879, and FAK is inhibited by 100 nM AG 879, but notby 10 nM AG879. The structure-function relationship analysis of AG 879 derivatives has revealed that both thio and tert-butyl groups of AG 879, but not (thio) amide group, are essential for its biological function (blocking the ETK-PAK1 pathway), suggesting that through the (thio) amide group, AG 879 can be covalently linked to agarose beads to form a bioactive affinity ligand useful for identifying the primary target of this drug.
KW - AG879
KW - ETK
KW - PAK
KW - RAS
KW - Transformation
UR - http://www.scopus.com/inward/record.url?scp=3142520112&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3142520112&partnerID=8YFLogxK
M3 - Article
C2 - 14726663
AN - SCOPUS:3142520112
VL - 3
SP - 96
EP - 101
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
SN - 1538-4047
IS - 1
ER -