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Flashcards in med chem Deck (47):
1

two main ways anti metabolites fight cancer

-inhibit nucleotide metabolism
-get incorporated into DNA

2

5-FU resembles which bases

uracil
thymine

3

antimetabolites are all what

prodrugs

4

potential resistance mechanism of all antimetabolites

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

5

thymidylate synthase does what

converts dUMP to TMP

6

5-FU mechanism

is a substrate of thymidylate synthase and gets incorporated into DNA

7

enzyme that degrades 5-FU

dihydropyrimidine dehydrogenase (DPD)

8

5-FU ADME

low oral bioavailability
short half life

9

how to increase 5-FU bioavailability

make a prodrug

10

5-FU prodrug

capecitabine

11

how is cisplatin activated

exchange the chloride with water

12

most reactive position in DNA

guanine N-7

13

intercalator drugs

mitoxantrone
doxorubicin

14

how do intercalator drugs work

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

15

what makes intercalator drugs have cardio toxicity

quinone

16

where do taxanes bind

inner surface of microtubules

17

how to taxanes work

-stabilize microtubules
-inhibit mitosis
-cause cell death

18

vinca alkaloids do what at high concentrations

bind alpha,beta-tubulin dimers and destabilize microtubules

19

vinca alkaloids do what at low concentrations

interfere with microtubule dynamics

20

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

tyr
ser
thr

21

protein kinase inhibitors mostly target what

tyrosine kinases

22

active site of tyrosine kinases are... (structural feature)

highly rigid

23

ion needed for activation of phosphates for hydrolysis

magnesium

24

features of the inactive conformation of kinases

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

25

features of the active conformation of kinases

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

26

type 1 kinase inhibitor MoA

binds ATP pocket in active conformation

27

type 2 kinase inhibitor MoA

binds ATP pocket in inactive conformation

28

type 3 kinase inhibitor MoA

binds allosteric site

29

type 4 kinase inhibitor MoA

binds to distant site

30

what makes selective inhibition difficult

active site is largely conserved among kinases

31

one benefit of having a nonselective kinase inhibitor

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

32

bcr-abl is responsible for what

chronic myeloid leukemia

33

part of the kinase that is responsible for selectivity

gatekeeper

34

4 design principles of kinase inhibitors

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

35

common sites of mutation resistance to imatinib

a-loop
p-loop
hinge

36

nilotinib features

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

37

what type of kinase inhibitor is dasatinib

type 1

38

what type of kinase inhibitor is imatinib

type 2

39

what interaction is critical for activity of imatinib

hydrogen bonding to thr315

40

only bcr-abl inhibitor effective for T315 mutants

ponatinib

41

reaction that covalent inhibitors use

michael addition

42

types of inhibitors that have increased selectivity

allosteric and covalent

43

bispecific antibodies

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

44

toxicity of Ab drugs compared to other anticancers

Abs carry most toxic compounds

45

3 regions of Ab drugs

Ab
linker
drug

46

types of linkers

hydrazone
disulfide
non-cleavable

47

major issue with Ab drugs

penetration of Abs through the whole tumor