med chem

Question 1

two main ways anti metabolites fight cancer

Answer 1

• inhibit nucleotide metabolism

- get incorporated into DNA

Question 2

5-FU resembles which bases

Answer 2

uracil

thymine

Question 3

antimetabolites are all what

Answer 3

prodrugs

Question 4

potential resistance mechanism of all antimetabolites

Answer 4

down regulation of metabolic enzymes which are needed to activate the drug

Question 5

thymidylate synthase does what

Answer 5

converts dUMP to TMP

Question 6

5-FU mechanism

Answer 6

is a substrate of thymidylate synthase and gets incorporated into DNA

Question 7

enzyme that degrades 5-FU

Answer 7

dihydropyrimidine dehydrogenase (DPD)

Question 8

5-FU ADME

Answer 8

low oral bioavailability

short half life

Question 9

how to increase 5-FU bioavailability

Answer 9

make a prodrug

Question 10

5-FU prodrug

Answer 10

capecitabine

Question 11

how is cisplatin activated

Answer 11

exchange the chloride with water

Question 12

most reactive position in DNA

Answer 12

guanine N-7

Question 13

intercalator drugs

Answer 13

mitoxantrone

doxorubicin

Question 14

how do intercalator drugs work

Answer 14

they stack in between bases of DNA using the quinone group, inhibiting topoisomerase II

Question 15

what makes intercalator drugs have cardio toxicity

Answer 15

quinone

Question 16

where do taxanes bind

Answer 16

inner surface of microtubules

Question 17

how to taxanes work

Answer 17

• stabilize microtubules
• inhibit mitosis
• cause cell death

Question 18

vinca alkaloids do what at high concentrations

Answer 18

bind alpha,beta-tubulin dimers and destabilize microtubules

Question 19

vinca alkaloids do what at low concentrations

Answer 19

interfere with microtubule dynamics

Question 20

amino acids that get phosphorylated by kinases and are commonly used by growth factors

Answer 20

tyr
ser
thr

Question 21

protein kinase inhibitors mostly target what

Answer 21

tyrosine kinases

Question 22

active site of tyrosine kinases are… (structural feature)

Answer 22

highly rigid

Question 23

ion needed for activation of phosphates for hydrolysis

Answer 23

magnesium

Question 24

features of the inactive conformation of kinases

Answer 24

-a-loop partially occupies ATP binding pocket and substrate binding is blocked

Question 25

features of the active conformation of kinases

Answer 25

- a-loop folded onto ATP binding site - DFG flipped inwards - p-loop binds phosphates

Question 26

type 1 kinase inhibitor MoA

Answer 26

binds ATP pocket in active conformation

Question 27

type 2 kinase inhibitor MoA

Answer 27

binds ATP pocket in inactive conformation

Question 28

type 3 kinase inhibitor MoA

Answer 28

binds allosteric site

Question 29

type 4 kinase inhibitor MoA

Answer 29

binds to distant site

Question 30

what makes selective inhibition difficult

Answer 30

active site is largely conserved among kinases

Question 31

one benefit of having a nonselective kinase inhibitor

Answer 31

single mutations are not as effective as a resistance mechanism *sunitinib

Question 32

bcr-abl is responsible for what

Answer 32

chronic myeloid leukemia

Question 33

part of the kinase that is responsible for selectivity

Answer 33

gatekeeper

Question 34

4 design principles of kinase inhibitors

Answer 34

- interaction with hinge region - gatekeeper controls selectivity - target hydrophobic pocket - bind allosteric pocket near ATP binding site

Question 35

common sites of mutation resistance to imatinib

Answer 35

a-loop p-loop hinge

Question 36

nilotinib features

Answer 36

- more potent that imatinib | - hydrophobic, so less sensitive to H-bonding mutations

Question 37

what type of kinase inhibitor is dasatinib

Answer 37

type 1

Question 38

what type of kinase inhibitor is imatinib

Answer 38

type 2

Question 39

what interaction is critical for activity of imatinib

Answer 39

hydrogen bonding to thr315

Question 40

only bcr-abl inhibitor effective for T315 mutants

Answer 40

ponatinib

Question 41

reaction that covalent inhibitors use

Answer 41

michael addition

Question 42

types of inhibitors that have increased selectivity

Answer 42

allosteric and covalent

Question 43

bispecific antibodies

Answer 43

chimeras of two Abs - one targets cancer marker - other recruits immune cells

Question 44

toxicity of Ab drugs compared to other anticancers

Answer 44

Abs carry most toxic compounds

Question 45

3 regions of Ab drugs

Answer 45

Ab linker drug

Question 46

types of linkers

Answer 46

hydrazone disulfide non-cleavable

Question 47

major issue with Ab drugs

Answer 47

penetration of Abs through the whole tumor