Approximately 10–20% of current FDA‐approved drugs target nuclear receptors. These drugs have a market value of 30 billion dollars per year.
Nuclear Receptors
Nuclear receptors (NRs) are proteins that function to regulate genes. There are 48 nuclear receptors in the body that have a similar structure. Some nuclear receptors are regulated by specific ligands that bind to the ligand binding domain (LBD). When a ligand binds to the ligand binding domain the nuclear receptor becomes able to bind to as region on a regulated gene called a response element via its DNA binding domain. After the NR is tethered to a gene a group of coregulatory proteins become associated with the NR to form a large complex that leads to gene activation or repression. This leads to an increase or decrease in proteins in the cells changing the activity of the cell. For some NRs no ligands have been identified. These NRs are known as orphan receptors.
The diverse action of NRs made them a major target for drugs. Nuclear receptors are involved in regulating numerous critical functions in the body including metabolism, inflammation, reproduction, cell proliferation, development and differentiation, and xenobiotic transformation. Approximately 10–20% of current FDA‐approved drugs target nuclear receptors. These drugs have a market value of 30 billion dollars per year. The major nuclear receptors targeted by drugs are the estrogen, androgen, glucocorticoid, progesterone, peroxisome proliferator-activated receptor and thyroid hormone receptors. Our major NR target for drugs is the estrogen receptors (ERs). The major indications for ER target drugs are contraception, menopausal symptoms, vaginal dryness and atrophy, osteoporosis, and the treatment and prevention of breast cancer. There are several classes of drugs approved by the FDA that target ERs shown below. Several classes are still in preclinical development.
“You would not expect your latch-key to open your neighbor’s door as well.” Erwin Schrodinger
— Erwin Schrodinger
Drugs that target ERs
Estrogen agonists
These are estrogens in oral contraceptive pills and menopausal hormone therapy (MHT) formulations. These drugs bind to the estradiol binding site on ERs present in the nucleus of the cells. They alter cellular functions mainly by regulating the activity of genes. Estrogen agonists are highly effective drugs, but they can cause serious side-effects. When used in MHT they increase the risk of breast and endometrial cancer.
Selective estrogen receptor modulator
These drugs bind to the same site on ERs as estrogen agonists, but because of differences in structures SERMs can act as agonists in some tissues and antagonist in other tissues. Tamoxifen and raloxifene are the most commonly prescribed SERMs. The SERMs mimic the agonist effect of estrogens in bone increasing bone mineral density and preventing bone fractures. Tamoxifen is used to prevent and treat breast cancer. Raloxifene is used to prevent osteoporosis and breast cancer.
Estrogen receptor downregulators
These drugs bind to ERs to degrade the receptor protein. Once ERs are degraded estrogens can no longer bind and activate the receptor to promote cell proliferation. Fulvestrant is the major ER downregulator used for treating breast cancer.
ERα reprogramming ligands
These ligands represent a new class of drugs that regulate the activity of ERα. They do not bind to the estradiol binding site on ERα. These drugs work by changing the genes that are regulated by estrogens. These ligands prevent estrogen stimulation of breast cancer cells and the growth of the uterus. We are developing ERα reprogramming ligands as a combination drug with estradiol to use in menopausal hormone therapy. Estrogen agonists stimulate smooth muscle cell growth that cause fibroids and processes that lead to endometriosis. ERα reprogramming ligands are being evaluated to treat fibroids and endometriosis.
ERβ-selective ligands
ERβ-selective ligands work by activating ERβ much more than ERα. One potential use of ERβ-selective ligands is to treat menopausal symptoms such as hot flashes. We previously showed that an ERβ-selective preparation called Menopausal Formula 101 decreased hot flashes in women. ERβ-selective drugs can be used for breast cancer treatment and prevention. ERβ has been found to have anti-proliferative effects on breast cancer cells. We are developing ERβ-selective ligands for vaginal dryness.
The differences between the drugs that regulate ERs are summarized in the table:
