Drug design

Question 1

Flutamide

Answer 1

Bacteriostatic, anti-androgenic activity. Heptatoxic. Rarely used for prostate cancer.

Question 2

Nilutamide

Answer 2

Developed from glutamine. Less hepatotoxic.

Question 3

Bicalutamide

Answer 3

Binding mode to AR known. Introduced in 1995. Widely used.

Question 4

Enzalutamide

Answer 4

Approvde 2012. Now supplanting bicalutamide. Rare CNS toxicity. No agonist activity.

Question 5

What proteins does bicalutamide bind?

Answer 5

Arg and Asn

Question 6

4 main group of antimetabolite drugs

Answer 6

Folate antagonists, pyrimidine antognists, purine antagonists, sugar-modifed nucleosides

Question 7

Examples of folate antagonists

Answer 7

Methotrexate, non-classical lipophilic antifolates, pemetrexed, raltitrexed

Question 8

Examples of pyrimidine antagonists

Answer 8

5-fluorouracil, fluorodeoxyuridine, (FdURD), azacytidine

Question 9

Examples of purine antagonists

Answer 9

6-mercaptopurine, thioguanine, tiazofurin

Question 10

Examples of sugar-modified nucleosides

Answer 10

Cytarabine (Ara-C), fludarabine, gemcitibine

Question 11

Temozolomide

Answer 11

DNA methylating agent (O6 or N7 of guanine)

Question 12

Mitomycin C

Answer 12

Alkylation at N2 and N7 of guanine. Covalent DNA minor groove binder

Question 13

CPI (cyclopropapyrroloindoles)

Answer 13

Alyklate DNA at N3 adenine. CC-1065, adozelesin, bizelesin

Question 14

Pyrrolo(1,4)benzodiazepine (PBD) mechanism of action

Answer 14

Form reversible aminal bond between exocyclic NH2 of guanine and C11 on PBD

Question 15

Lipophilic antifolates

Answer 15

Enter cell by passive diffusion - RFC not needed. Pyrimethamine, nolatrexed, piritrexim, methylbenzoprim.

Question 16

Inhibitors of thymidylate synthase

Answer 16

Pemetrexed and raltitrexed. Bind at 5,10-CH2-tetrahydrofolate binding site

Question 17

Azacytidine

Answer 17

Analogue of cytidine (a nucleoside in DNA and RNA). Weak inhibitor of thymidylate synthase. Phosphorylated then incorporated into RNA. Unstable so decomposes causing DNA damage.

Question 18

Gemcitabine

Answer 18

Converted to triphosphate F2dCTP and diphosphate F2dCDP. Inhibits DNA polymerase as analogue of dCTP. 100x more potent than Ara-C

Question 19

Cytarabine (Ara-C)

Answer 19

Converted to triphosphate. Inhibits DNA polymerase, making it non-functional

Question 20

Fludarbine

Answer 20

Converted to triphosphate. Inhibits DNA polymerase as an analogue of dATP.

Question 21

Bevacizumab

Answer 21

Recombinant human monoclonal antibody, binds VEGF

Question 22

Diaminocyclohexane (DACH)

Answer 22

Contained in oxaplatin and aroplatin. Increase resistance to cells producing glutathione

Question 23

Aroplatin

Answer 23

Liposomal preparation of cisplatin like agents

Question 24

ProLindac

Answer 24

Cisplatin like drug lied to a water soluble biocompatible co-polymer. This should exploit the enhanced permeability and retention (EPR) effect of macromolecules in tumours

Question 25

Crizotinib

Answer 25

Inhibitor of ALK tyrosine kinase

Question 26

Imantinib

Answer 26

Inhibitor of ABL tyrosine kinase

Question 27

Iniparib

Answer 27

First PARP inhibitor to enter clinical trials. Non-specific thiol-reactive compound, ejects Zn2+ from Zn fingers

Question 28

Olaparib

Answer 28

Inhibits PARP-1, -2, -3. Approved for BRCA-mutant ovarian cancer.

Question 29

Rucaparib

Answer 29

Inhibits PARP-1, -2, tankyrase-1, -2. Approved for BRCA-mutant ovarian cancer.

Question 30

Veliparib

Answer 30

Inhibits PARP-1, -2, tankyrases

Question 31

Niraparib

Answer 31

Inhibits PARP-1, -2, -4, tankyrases

Question 32

Talazoparib

Answer 32

Inhibits PARP-1, -2. Pontent in cells by trapping PARP-1 at strand break.