Fulvestrant has a unique mechanism of action,16 comprising several different aspects (Fig. 3.10). In the first place, fulvestrant is a competitive inhibitor of estradiol binding at the ER, with an affinity of 89% that of estradiol. Another consequence of fulvestrant binding is the impairment of the dimerization of ER, an event that takes place after estrogen binding and is essential for the nuclear localization of the receptor. Because of the inhibition of dimerization, fulvestrant binding leads to accelerated receptor degradation due to the lower stability of the monomer.

On the contrary, the side chain of fulvestrant obstructs the folding of the H12 helix of the receptor and therefore prevents its interaction with coactivators, as mentioned in Section 2.1 (Fig. 3.11).

Figure 3.12 gives a summarized picture of the events associated to fully activated transcription by ER agonists, partially inactivated transcription by SERMs, and full inactivation by antiestrogens. In the first case (Fig. 3.12A), estradiol (E)

FIGURE 3.10 Mechanism of action of fulvestrant.

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