Cancer Research - Europa

Keywords | Epigenetics | gene regulation | histone modifi cation | small molecule inhibitors | cancer therapy |
SMARTER
Development of small modulators
of gene activation and repression
by targeting epigenetic regulators
Summary
The identity of a given cell within a metazoan organism is
primarily defi ned by the expression pattern of its genes. The
activation and repression of particular genes is tightly regulated
by the concerted action of transcription factors that
recognize and bind specifi c DNA sequences within regulatory
regions. Work done over the last 20 years revealed this
basic mechanism of gene activation and repression, while
recent experiments exposed an additional layer of regulation
involving modifi cations of DNA and bound histones.
These modifi cations are involved in cellular inheritance of
transcriptional states through cell division and development
and as they are not coupled to DNA sequence are referred
to as epigenetic. Many factors that impact on epigenetic
phenomena are clearly distinct from basic transcription factors
and are involved in regulating chromatin structure.
Modulation of chromatin structure is frequently achieved by
intrinsic enzymatic activities that either mark particular
regions within the genome for activity or repression or use
the hydrolysis of ATP to remodel nucleosomal arrays. This
variation of gene expression patterns in response to external
and internal signals has a major infl uence on stem cell differentiation,
the maintenance of tissue integrity and the
adaptation of organisms to environmental dynamics.
Recently, small molecule inhibitors that target chromatinmodifying
enzymes have been used for cancer treatment,
which has opened new avenues in therapeutical research.
The SMARTER project aims at the development and
im provement of such compounds, which is the primary
mission of Chroma, the SME participating in the consortium.
Problem
The epigenetic level of gene regulation is being analysed
intensively worldwide. However, the knowledge gained
from these studies has not been transferred to drugs or
drug candidates for the treatment of major diseases.
Equally, development of small molecules targeting epigenetic
regulators have so far not been the major focus of
drug discovery eff orts.
To pursue this promising approach it is obviously important
to further improve understanding how the eukaryotic
genome in general, and the human genome in particular,
operates. Therefore knowledge about its DNA sequence,
its epigenetic control systems and its dynamic structure in
relation to gene expression must be integrated.
BIOLOGY 75
Aim
The SMARTER project aims at the development and
improvement of compounds targeting epigenetic regulators.
These compounds will be tested in various assays
making it possible to collect data sets of several parameters
as histone modifi cations, chromatin states, gene expression
patterns and physiological characteristics in an integrative
manner for the fi rst time.
Therefore major objectives are:
• identifi cation of small molecule inhibitors that target
various histone-modifying enzymes;
• validation of these inhibitors through in vivo analytics of
histone modifi cations states;
• establishment of histone modifi cation states as standard
readouts for drugs that target epigenetic modifi ers;
• improvement of known epigenetic modulators through
medicinal chemistry;
• identifi cation of target genes that are regulated by the
SMARTER molecules;
• application of the SMARTER molecules in standard
animal model systems to verify their activity in living
organisms.
Expected results
Our proposal will thereby promote the development and
improvement of a new branch of cancer drugs and as well
support validation of new potential drug target enzymes.
Additionally, tools will be generated which allow new insights
in fundamental mechanisms of gene regulation by epigenetic
modifi cation.
Potential applications
In the context of human health, an understanding of gene
regulation is central to our understanding of many medical
complaints and conditions. Fundamental aspects of chromatin
function are increasingly recognized as important
factor in the development of many severe and often untreatable
diseases. Therefore many proteins that are involved in
the regulation of chromatin structure are potential drug targets
and small molecules directed against these factors will
play an increasingly important role in treating patients that
are aff ected by one of these maladies.
The cooperation between leading European chromatin labs
and Chroma is expected to greatly strengthen the SMEs
knowledge base and thereby having a strong impact on its
ability to enter drug candidates in clinical trials.