med chem Flashcards
two main ways anti metabolites fight cancer
- inhibit nucleotide metabolism
- get incorporated into DNA
5-FU resembles which bases
uracil
thymine
antimetabolites are all what
prodrugs
potential resistance mechanism of all antimetabolites
down regulation of metabolic enzymes which are needed to activate the drug
thymidylate synthase does what
converts dUMP to TMP
5-FU mechanism
is a substrate of thymidylate synthase and gets incorporated into DNA
enzyme that degrades 5-FU
dihydropyrimidine dehydrogenase (DPD)
5-FU ADME
low oral bioavailability
short half life
how to increase 5-FU bioavailability
make a prodrug
5-FU prodrug
capecitabine
how is cisplatin activated
exchange the chloride with water
most reactive position in DNA
guanine N-7
intercalator drugs
mitoxantrone
doxorubicin
how do intercalator drugs work
they stack in between bases of DNA using the quinone group, inhibiting topoisomerase II
what makes intercalator drugs have cardio toxicity
quinone
where do taxanes bind
inner surface of microtubules
how to taxanes work
- stabilize microtubules
- inhibit mitosis
- cause cell death
vinca alkaloids do what at high concentrations
bind alpha,beta-tubulin dimers and destabilize microtubules
vinca alkaloids do what at low concentrations
interfere with microtubule dynamics
amino acids that get phosphorylated by kinases and are commonly used by growth factors
tyr
ser
thr
protein kinase inhibitors mostly target what
tyrosine kinases
active site of tyrosine kinases are… (structural feature)
highly rigid
ion needed for activation of phosphates for hydrolysis
magnesium
features of the inactive conformation of kinases
-a-loop partially occupies ATP binding pocket and substrate binding is blocked
features of the active conformation of kinases
- a-loop folded onto ATP binding site
- DFG flipped inwards
- p-loop binds phosphates
type 1 kinase inhibitor MoA
binds ATP pocket in active conformation
type 2 kinase inhibitor MoA
binds ATP pocket in inactive conformation
type 3 kinase inhibitor MoA
binds allosteric site
type 4 kinase inhibitor MoA
binds to distant site
what makes selective inhibition difficult
active site is largely conserved among kinases
one benefit of having a nonselective kinase inhibitor
single mutations are not as effective as a resistance mechanism
*sunitinib
bcr-abl is responsible for what
chronic myeloid leukemia
part of the kinase that is responsible for selectivity
gatekeeper
4 design principles of kinase inhibitors
- interaction with hinge region
- gatekeeper controls selectivity
- target hydrophobic pocket
- bind allosteric pocket near ATP binding site
common sites of mutation resistance to imatinib
a-loop
p-loop
hinge
nilotinib features
- more potent that imatinib
- hydrophobic, so less sensitive to H-bonding mutations
what type of kinase inhibitor is dasatinib
type 1
what type of kinase inhibitor is imatinib
type 2
what interaction is critical for activity of imatinib
hydrogen bonding to thr315
only bcr-abl inhibitor effective for T315 mutants
ponatinib
reaction that covalent inhibitors use
michael addition
types of inhibitors that have increased selectivity
allosteric and covalent
bispecific antibodies
chimeras of two Abs
- one targets cancer marker
- other recruits immune cells
toxicity of Ab drugs compared to other anticancers
Abs carry most toxic compounds
3 regions of Ab drugs
Ab
linker
drug
types of linkers
hydrazone
disulfide
non-cleavable
major issue with Ab drugs
penetration of Abs through the whole tumor
