Nuclear Hormones Flashcards
Reasons why NRs are important targets for therapeutics
1) they regulate key processes (metabolism, circadian biology….)
2) All the processes they control are disrupted in disease
3) Good, simple target (rapid response to a specific issue)
Drug design to target NRs
Mimic ligands already known to bind the NR
- templates such as Cortisol (GR), Retinioc Acid (RXR), Oxysterol (LXR) and Estrogen (ER)
- companies alter ligand structure to design new drugs (13% of FDA approved drugs target NRs)
Therapeutic applications: Replacement
Synthetic versions of the endogenous ligand are made to have improved pharmacokinetics
- e.g. Synthetic Vitamin D = Ergocalciferol
Therapeutic applications: Activity Modulators
Making a synthetic ligand with a greater potency than the endogenous type.
Making/selecting for improved therapeutic qualities in NR treatments from template molecules
The endogenous ligand has lots of different little systematic changes made to alter its structure
- A screening assay can be done to select for the higher potency (using a luciferase assay, stronger binding = increased luminescence)
Making a synthetic NR antagonist (no template available)
Commonly found accidentally when screening for agonist (inhibiting binding/receptor activation)
- used when root problem of disease is from constant NR activation
e. g. Tamoxifen
- estrogen receptor agonist/antagonist
- used in treating breast cancer
Therapeutic applications: Selective modulators
Making a compound that binds the surface of the LBD to prevent CoA or CoR recruitment
- limiting coregulator recruitment blocks effects of NRs
- early days in research
Estrogen Receptors normal role and distribution of expression
Estrogen Receptors are important for development, increasing cell proliferation and inhibiting apoptosis (loss of regulation = cancer!)
- Due to high proliferative nature, its expression is limited to certain tissues
Loss of Estrogen Receptor Agonist (ERA) signalling
Can lead to cancer
- mutation can cause constituent activation
- high expression levels cause strong responses even if ligand levels are normal
Environmental factors increasing risk of breast cancer
Endocrine Disrupting Chemicals (EDCs) from foods, plastics, cosmetics… are believed to increase NR activation by binding to their LBD
- currently over 14,000 ECDs identified
Breast cancer
Most common (1:8 women in UK) cancer in women. Involves expression of 3 receptors to classify the cancer:
1) Estrogen Receptor (ERA) & Progesterone receptor
- 70% of cases, treated with hormone therapy
2) Human Epidermal Growth factor 2 (HER2)
- 20% of cases, treated with biological therapy (monoclonal antibodies)
3) Basal-like/triple negative
- 10% of cases, treated with surgery & chemo only
Treating ERA-positive, luminal breast cancer:
Preventing estrogen production
Aromatase inhibitors prevent estrogen production
e. g. Anastrozole
- blocks biosynthetic pathway from cholesterol to estrogen by preventing ERA activation (held in cytoplasm)
- Side effects: no estrogen drives ‘medical menopause’
Treating ERA-positive, luminal breast cancer:
ERA antagonists
Anti-estrogens - ERA antagonists
- Don’t activate ERA but compete with estrogen to prevent it binding
- Affects all estrogen responsive tissues so also causes ‘medical menopause’
Treating ERA-positive, luminal breast cancer:
Selective Estrogen Receptor Modulator (SERM)
Works to inhibit ERA in breast tissue but not in other tissue
e. g. Tamoxifen:
- In breast, is an antagonist as it drives conformational change to bind NCoR (inhibiting survival/proliferation)
- In other tissue, it’s agonistic as its conformational change binds SRC-1 to activate survival/cell cycle progression
Reason for different responses: more NCoR in breast, more SRC-1 elsewhere
Treating Triple Negative Breast Cancer (TNBC) NRs
No ERA or PR expressed however a lot of Glucocorticoid Receptors (GR) and Androgen Receptors (AR) are expressed
Higher AR & GR = shorter survival projection
Targeting these receptors can provide treatment (drugs already in clinical use)
GR modulators to treat Chronic Inflammation
GR expressed in almost all tissue types, activated by ligand Cortisol (CORT)
- ligand levels (control step) controlled by HPA axis (body clock regulated)
- CORT made in adrenal glands and secreted into circulation, acting on peripheral tissues as well as pituitary/hypothalamus to switch OFF its own production
Role of CORT
1) Homeostasis
- sets body clock and gives morning boost
- increases metabolism, cerebral blood flow….
2) Stress, injury and infection
- activates immune response and some inflammation
- can turn off immune response
Clinical use of synthetic glucocorticoids (and production?)
Anti-inflammatories
- Act on all tissues of body (1st line of defence)
Solid tumour therapy
- reduce swelling before/after surgery
- reduce inflammation from chemo
Developed by making small changes to endogenous molecule to increase potency and affinity (causes some major side effects)
Side effects of synthetic glucocorticoids
Come as the endogenous Glucocorticoids (Gc) work in pulses but synthetic are constant
- insomnia
- hypertension & glaucoma (overincreased muscle tone)
- Drives insulin resistance
- suppress immune system
Avoiding side effects of synthetic Gc treatment
1) Restrict delivery: no systemic application, just target site:
- topical cream, inhaled (brown inhaler success story), eye drop, injection
2) Restict response: develop selective steroids
- success with treating breast cancer (SERM)
- aiming to prevent GR in homodimer form (which affects metabolism) but to promote in monomer form (anti-inflammatory therapeutic effects)
