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Welcome, everyone,
to Chapter 8 of
this short talk series on
nuclear receptors as
therapeutic targets.
Before starting to look at
the individual receptors
in Chapter 9 and the
following chapters,
Chapter 8 will give
an overview of
how nuclear receptors
evolved as drug targets.
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We have seen in the
last chapter that
several nuclear receptors are
binding hormones as
natural ligands.
The history of nuclear
receptors somewhat started with
the discovery of hormones
in the early 20th century,
but it took until the 1960s that
it was found that
estrogens bind to
an intracellular protein that
translocates to the nucleus
after ligand binding,
and that steroid and
thyroid hormones regulate
mRNA synthesis of
specific proteins.
Another decade later,
the estrogen receptor was cloned
as the first nuclear receptor,
and it was found that
the steroid hormone
receptors interact
with specific
promoters on the DNA
and lead to modification
of chromatin organization.
In the 1980s,
many nuclear receptors were
identified and classified
as a superfamily of ligand-activated
transcription factors
and also RXR was discovered
as a universal
heterodimer partner.
In the 1990s and early 2000s,
the first nuclear receptor
crystal structures were solved,
the system of co-activators and
co-repressors was discovered,
and nuclear receptor
phosphorylation was observed
linking membrane
receptor signaling
and nuclear receptor signaling.
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Hormones were used
as drugs before
their receptors and
mechanisms were known.
The first fully synthetic
nuclear receptor ligand drug
was the estrogen receptor
modulator clomiphene in 1967,
and troglitazone as the
first drug targeting
a non-steroid hormone
nuclear receptor
was approved in 1997.
Since then, several drugs
targeting nuclear receptors
have been developed,
making the family a very
successful class of drug targets.
