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Message: Epigenetic Primer
There was a post on IV by rndtbl on July 9th that I have pasted below. It explains readers, writers and erasers in layman friendly language and gives Resverlogix a plug for their advanced epigenetic approach.
The following message was updated on 7/9/2018 8:28:35 AM.
2018 Biotech Primer Weekly Compendium pgs.35-36 Resverlogix
2 0 1 8 B I O T E C H P R I M E R W E E K L Y C O M P E N D I U M 3 7
BREAKING IT DOWN
Epigenetic drugs are small molecule drugs that target
epigenetic regulators, or proteins that write, read, or
erase epigenetic modifications.
• Writers are the enzymes that make the chemical
modifications — methylation or acetylation
as described above — to DNA molecules or
histone proteins.
• Erasers are enzymes that remove these
chemical groups.
• Readers are the proteins that detect and respond to
these modifications, causing the DNA to be more or
less tightly wrapped around the histone protein. Any
one of these proteins could be inhibited or activated
to affect changes in epigenetic modifications.
OLD SCHOOL: WRITING & ERASING
The disease that has been best classified in terms of
epigenetic variations is cancer. Currently, there are five
epigenetic drugs on the market to treat cancer, and more in
development. Those on the market fall into two categories:
• Histone deacetylase (HDAC) inhibitors: HDACs are
erasers — they remove acetyl groups from histone
proteins, resulting in increased expression of
associated genes. Three HDAC inhibitors have been
approved by the FDA: Zolinza (Merck; Kenilworth,
NJ) and Istodax (Celgene; Summit, NJ) both treat
cutaneous T-cell lymphoma, and Farydak (Novartis;
Basel, Switzerland) for the treatment of multiple
myeloma. HDAC inhibitors in development include:
• DNA-methyltransferase (DNMT) inhibitors: DNMT’s are
writers — they add methyl groups to DNA, resulting
in decreased expression of associated genes. Two
DNMT inhibitors have been approved by the FDA:
Vidaza (Celgene) and Dacogen (Otsuka; Tokyo,
Japan). Both drugs are used to treat myelodysplastic
syndrome and acute myeloid leukemia.
• Histone-methyltransferase (EZH2) inhibitors: EZH2’s
are also writers — these enzymes transfer methyl
groups to histone proteins. One EZH2 is associated
with over activity in a number of different cancers.
There are no EZH2 inhibitors currently approved, but
several are in development, including Constellation
Pharmaceuticals’ (Cambridge, MA) CPI-1205
in Phase I for advanced B-cell lymphomas, and
Epizyme’s (Cambridge, MA) tazemat, currently
in Phase II for non-Hodgkin lymphoma, certain
genetically-defined solid tumors, and mesothelioma.
THE NEW CLASS: READERS
A class of proteins called “Bromodomain and Extra
Terminal motif” (BET) proteins are reader proteins. They
recognize and bind to specific patterns of acetylation on
histone proteins. Upon binding, they recruit additional
proteins that regulate gene activity. Irregularities in
histone acetylation, then, may send the wrong message
to a BET protein. By inhibiting the interaction between
BET protein and histone proteins, researchers have
found that they can prevent incorrect messages from
being received by the BET proteins. Currently, there
are no BET inhibitors (BBI) approved, but several are in
clinical development.
The farthest along is Resverlogix’s
(Calgary, Canada) apabetalone, which is in Phase III
testing for atherosclerosis and associated cardiovascular
disease. Additional BBIs in clinical development are
shown in the table below:
Epigenetics promises to change the way we look at the
human genome. Scientists have made great strides in
understanding how epigenetic modifications contribute
to both health and disease; however, a complete
understanding of these modifications is still very much a
work in progress. As that work develops, researchers will
undoubtedly uncover new drug targets and approaches
to disease management. Stay tuned!
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