Estrogen plays a major part in the stimulation of breast cancer cell proliferation in hormone-dependent breast cancer. High concentrations of estrogen seem to promote the development of breast cancer. Consequently, two main approaches to control and block the pathological activity of estrogens have been developed. The first approach focuses on the inhibition of estrogen action by antiestrogens, which interact with the estrogen receptors. The second focuses on directly inhibiting estrogen production by inhibiting the estrogen synthetase aromatase.<unk> s are identified as Type I inhibitors which interact with the substrate-binding site of the aromatase enzyme. Figure 5: Aromatase Figure 6: Estrogen biosynthetic pathway The aromatase enzyme Aromatase is a cytochrome P450 which catalyzes three consecutive hydroxylation reactions, converting C19 androgens to aromatic C18 estrogens. After gaining electrons from NADPH-cytochrome P450 reductase, the aromatase converts androstenedione and testosterone to estrone and estradiol, respectively. The aromatization of androgen is the terminal and rate-limiting step in estrogen synthesis. Recent studies have focused on defining the active site region of the aromatase enzyme and to evaluate the most promising reaction mechanism. Three-dimensional models of the aromatase active region have also been generated, though the exact nature of the structure has not yet been fully defined. Figure 7: General reaction of the conversion of testosterone to estradiol catalyzed by aromatase Figure 8: Catalytic mechanism of aromatase Figure 9: Structure of 17-hydroexemestane Steroidal structure Drugs like exemestane and other<unk> s have a steroidal structure that competes with the natural aromatase substrate androstenedione. The inhibitor must share important structural features with the endogenous substrate, and as features of the androgens, allowing them to interact with the catalytic site on the enzyme protein. This renders the<unk> s inherently selective. Due to its selective inhibition it will not affect the production of the other steroids in the estrogen biosynthetic pathway. Binding to the active site The drugs bound to the catalytic site are often metabolized to intermediates which have much higher affinity for the androgen receptor. The binding of the intermediate metabolite 17-hydroexemestane for the androgen receptor is about 100 times that of the parent compound, exemestane. When the metabolite attaches to the active site on the enzyme, the enzyme initiates its typical sequence of hydroxylation, but hydroxylation produces an unbreakable covalent bond between the inhibitor and the enzyme protein. Even if all unattached parts of the inhibitor are removed, the enzyme activity of the aromatase can only be restored by new enzyme synthesis. The inhibitor thereby blocks the activity of the enzyme even after the drug is cleared from circulation, thus having a lasting effect in vivo. There is no need for continued presence of the drug to maintain inhibition, which in turn reduced the chance of toxic adverse effects to the patient. Due to the irreversible nature of the inhibition, the steroidal AIs are often marketed as inactivators or suicide inhibitors.
Steroidal aromatase inhibitor
Selective estrogen receptor degrader
Aromatase inhibitor
Selective androgen receptor modulator
Selective androgen receptor degrader
N-Terminal domain antiandrogen
Steroidal antiandrogen
Antiestrogen