444
Antitumor Steroids
O
N
O
O
OH
C
O
O
NH
O
HN
H
N
O
HN
NH
O
Glu353
Arg394
Antiestrogenic
side chain
O
O
H
N
C
O
O
3.8 Å
Asp351
Fig. 4
Docking of OH-Tam (partial antiestrogen) in the ER
α
-HBD. The
phenolic ring of OH-Tam is located in the HBD by Glu353 and Arg394, in
analogy with the A-ring of E
2
(see Fig. 3). The nitrogen atom of the amino alkyl
side chain of OH-Tam weakly interacts with Asp351. This interaction seems to
be the key to the antagonistic activity of the compound.
However, in the hormone binding pocket,
binding of OH-Tam to ER promotes a
conformational change differing from that
driven by E
2
inasmuch as the orientation
of H12 appears essentially different. In the
OH-Tam–ER complex, H12 is oriented in
such a way that it maintains the pocket
wide open, allowing the speciFc interac-
tion of the nitrogen atom of the side chain
of OH-Tam with a residue of the binding
pocket (Asp351). In this ‘‘open conforma-
tion’’, which is stabilized by the side chain
of the antiestrogen, H12 occupies a part of
a coactivator binding site, which normally
becomes accessible upon E
2
exposure. As
a consequence, OH-Tam-associated H12
reorientation abrogates the recruitment of
coactivators perhaps in favor of corepres-
sors (A±-2 silencing). Hence, interaction
between the side chain of OH-Tam and
Asp351 seems to be the key to the antago-
nistic activity of the compound. Note that
this open conformation of the HBD allows
the expression of other transcriptional ac-
tivating sites (A±-1 and to some extent
A±-2b) explaining the partial estrogenicity
of OH-Tam.
OH-Tam belongs to an important class
of clinically relevant compounds, recog-
nized now as
selective estrogen receptor mod-
ulators
(SERMs). These compounds act as
antagonists or agonists, depending on the
cellular type promoters and coregulators
(ER isoform is also of importance). A sec-
ond class of antagonists, (ICI 182,780, ICI
164,384 and RU 58,668; ±ig. 5) are capable
of completely blocking the transcriptional
activity of ER via the inhibition of both
A±1 and A±2 action. One may speculate
that these ‘‘pure antiestrogens’’ could play
an important role as a second-line therapy
against advanced breast cancer in patients
who develop resistance to tamoxifen treat-
ment. They correspond to 7
α
or 11
β
derivatives of E
2
in which speciFc reactive
groups are linked to the steroidal moiety
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