Androgen Receptor

Question 1

Sources of androgen?

Answer 1

Testes (90-95), adrenal glands, prostate cells themselves

Question 2

Structure of AR?

Answer 2

8 exons, 4 structural parts (NTD transactivation domain, DNA binding domain, hinge region, CT ligand binding domain).

Question 3

AR and TST

Answer 3

AR sits at cytoplasm when not associated with androgen, upon androgen binding an inhibitory chaperone protein moves away.
AR goes to nucleus and undergoes homo-dimerization, binds to androgen responsive DNA… gene expression!
Therapeutically we want to block AR and TST from associating so you can prevent gene trx.

Question 4

Resistance to endocrine therapy?

Answer 4

How do you escape hormone therapy/antagonists?
1.) AR activation of non-gonadal TST
2.) Over-expression of AR
3.) AR mutation leads to promiscuous AR activation
4.) Truncated AR now has constitutively active ligand binding domain
basically too many receptors, or they are active w/o hormones

Question 5

Abiraterone

Answer 5

Used for formerly hormone resistant therapy.
It acts on cytochrome 17, which is important in androgen production. It works because you stop TST production from 3 sources. 2011.

Question 6

Enzalutamide

Answer 6

Targets AR directly.
Antagonistic.
It inhibits nuclear translocation… inhibits DNA binding of AR.
Does not have partial agonist properties which other drugs have. 2012.