Nuclear Hormones Flashcards

1
Q

Reasons why NRs are important targets for therapeutics

A

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)

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2
Q

Drug design to target NRs

A

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)
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3
Q

Therapeutic applications: Replacement

A

Synthetic versions of the endogenous ligand are made to have improved pharmacokinetics

  • e.g. Synthetic Vitamin D = Ergocalciferol
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4
Q

Therapeutic applications: Activity Modulators

A

Making a synthetic ligand with a greater potency than the endogenous type.

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5
Q

Making/selecting for improved therapeutic qualities in NR treatments from template molecules

A

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)

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6
Q

Making a synthetic NR antagonist (no template available)

A

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

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7
Q

Therapeutic applications: Selective modulators

A

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
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8
Q

Estrogen Receptors normal role and distribution of expression

A

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

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9
Q

Loss of Estrogen Receptor Agonist (ERA) signalling

A

Can lead to cancer

  • mutation can cause constituent activation
  • high expression levels cause strong responses even if ligand levels are normal
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10
Q

Environmental factors increasing risk of breast cancer

A

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
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11
Q

Breast cancer

A

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

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12
Q

Treating ERA-positive, luminal breast cancer:

Preventing estrogen production

A

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’

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13
Q

Treating ERA-positive, luminal breast cancer:

ERA antagonists

A

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’
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14
Q

Treating ERA-positive, luminal breast cancer:

Selective Estrogen Receptor Modulator (SERM)

A

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

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15
Q

Treating Triple Negative Breast Cancer (TNBC) NRs

A

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)

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16
Q

GR modulators to treat Chronic Inflammation

A

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
17
Q

Role of CORT

A

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

18
Q

Clinical use of synthetic glucocorticoids (and production?)

A

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)

19
Q

Side effects of synthetic glucocorticoids

A

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
20
Q

Avoiding side effects of synthetic Gc treatment

A

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)