Sunday November 22 2009 | Biotechnology feed | All feeds
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Sunday November 22 2009 | Biotechnology feed | All feeds
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A-161906 a TGF-beta-like agonist that acts via histone deacetylase inhibition The need for
improved treatments of cancer has driven the development of a number of
strategies designed to regulate transcription. The retinoic acids represent
one early target that has still to be fully exploited. Histone deacetylation
represents a second area of transcriptional control receiving much interest.
This field centers on the now generally accepted view that chromatin structure
is plastic and that histone (de)acetylation regulates genome structure and
hence expression. Modifying this process by histone deacetylase (HDAC)
inhibitors can therefore regulate, potentially in a highly specific manner,
transcription thereby offering a much more targeted approach to cytostasis
than currently available. Information relating to histone deacetylation is
emerging with breathtaking rapidity with over 1 new article currently being
published every day. In response to this activity we recently published a
comprehensive overview of the pharmaceutical potential of HDAC inhibitors . Transforming
growth factor beta (TGF-beta) is a multifunctional protein that has been shown
to possess potent growth-inhibitory activity. Researchers at Abbott
laboratories have recently identified a series of small molecular weight
compounds with TGF-beta-like activities. These biaryl hydroxamate compounds
(for example A-161906) demonstrated complete TGF-beta-like agonist activity
and inhibited the proliferation of multiple cell lines in a
concentration-dependent manner. Cells were growth arrested at the G1-S
checkpoint similar to TGF-beta. Consistent with the G1-S arrest, A-161906
induced the expression of the cyclin-dependent kinase inhibitor p21waf1/cip1.
A-161906 produced many cellular effects similar to that of TGF-beta but did
not displace labeled TGF-beta from its receptors. Cells with mutations in
either of the TGF-beta receptors I or II were growth-arrested by A-161906.
Therefore, the site of action of A-161906 appears to be distal to the
receptors and possibly involved with the signaling events controlled by TGF-beta.
The TGF-beta mimetic effect of A-161906 can be partially, if not entirely,
explained by its activity as a HDAC inhibitor. A-161906 demonstrated potent
HDAC-inhibitory activity once again supporting the therapeutic importance of
HDAC inhibitors. Despite the level of experimental research surrounding the
HDACs, A-161906 represents one of only a small group of HDAC inhibitors in
drug development and this research is therefore important with respect to
therapeutic possibilities. Adapted from Glaser et al, Mol Cancer Ther 2002 Aug;1(10):759-68.
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