Anti-Androgens

Question 1

What are the stages of prostate cancer?

Answer 1

Normal prostatic epithelium.
Low grade prostatic intraepithelial neoplasia.
High grade prostatic intraepithelial neoplasia.
Metastatic prostate cancer.
Androgen-independent cancer.

Question 2

What are the treatment options for prostate cancer?

Answer 2

Active surveillance
Surgery 
Hormone therapy 
Chemotherapy
High intensity focused ultrasound
External beam radiotherapy
Permanent seed brachytherapy

Question 3

How does testosterone promote proliferation?

Answer 3

Testosterone binds to the androgen receptor which causes conformational change in the AR. This complex translocates to the nucleus, where it signals for proliferation.

Question 4

What are examples of first generation drugs which bind to androgen receptor?

Answer 4

Flutamide
Nilutamide
Bicalutamide

Question 5

What are examples of second generation androgen receptor antagonists?

Answer 5

Enzalutamide, Daralutamide and Apalutamide

Question 6

How does bicalutamide act at androgen receptors?

Answer 6

It binds to the receptor but does not cause a conformational change. the testosterone is blocked from binding. The bicalutamide-androgen receptor complex is internalised but cannot translocate to the nucleus. Bicalutamide has some agonist activity, especially at mutant androgen receptors.

Question 7

How does enzalutamide act at androgen receptors?

Answer 7

It binds to the receptor but does not cause a conformational change. the testosterone is blocked from binding. The enazlutamide-androgen receptor complex is internalised but cannot translocate to the nucleus. Enazlutamide has no agonist activity.

Question 8

How does testosterone bind?

Answer 8

Through hydrogen bonds and hydrophobic interactions

Question 9

How does bicalutamide bind to the androgen receptor?

Answer 9

It binds through H bonds to Arg752.
It does not hydrogen bond to Thr877.
It binds through hydrogen bonds to Asn705

Question 10

How does flurophenyl bind to androgen receptor?

Answer 10

It binds in the hydrophobic side pocket.

Question 11

What are the mechanisms of resistance to enzalutamide?

Answer 11

AR signalling pathway alternation
AR mutation
AR splice variants
Metabolic changes 
Lineage plasticity

Question 12

What are drugs that inhibit CYP17A1?

Answer 12

Ketoconazole
Abiraterone
Abiraterone acetate

Question 13

How does progesterone bind to CYP17A1?

Answer 13

The C=O forms a hydrogen bond to Asn202. The hydrocarbon part of the steroid binds to the hydrophobic side chains.

Question 14

How does abiraterone bind to CYP17A1?

Answer 14

OH forms H-bond to Asn202. The hydrocarbon part of the drug binds to the hydrophobic side chains.