Kinase Inhibitors Flashcards
1
Q
2 types of protein kinases?
A
tyrosine kinases
serine-threonine kinases
2
Q
Where are cytoplasmic (non-receptor kinases) located?
A
inside the cell
3
Q
Are receptor kinases transmembrane proteins?
A
yes - have intracellular domain and extracellular (ligand binding domain)
4
Q
Abnormal activation of kinases arises from a single type of genetic change.
a. true
b. false
A
b. false
arises from MULTIPLE types of genetic changes
5
Q
The vast majority of kinase inhibitors ___ target the ATP binding site.
a. competitively
b. non-competitively
A
a. competitively
6
Q
What do small molecule kinase inhibitors have that makes key contacts with the hinge region (adenine pocket)?
A
H-bond acceptors and/or H-bond donors
7
Q
What is the pharmacophore, or “warhead” for irreversible kinase inhibitors?
A
alpha beta unsaturated amide
8
Q
The molecular weight of small molecule kinase inhibitors are generally __ than many other orally available drug classes.
a. higher
b. lower
A
a. higher
most have molecular weight >=450
9
Q
Do small molecule kinase inhibitors have high or low protein binding?
A
high protein binding
10
Q
Small molecule kinase inhibitors are generally __ lipophilic than many other drug classes.
a. less
b. more
A
b. more
most have log P >=3
11
Q
Many kinase inhibitors have what AE?
A
QT interval prolongation
12
Q
What CYP often plays a role in kinase metabolism?
A
3A4
13
Q
The Philadelphia chromosome is caused by a reciprocal translocation between what chromosomes?
A
9 and 22
14
Q
What is the cause of > 90% of chronic myelogenous leukemia (CML)?
A
Philadelphia chromosome
15
Q
What is target of imatinib?
A
BCR-ABL
16
Q
What can imatinib promote?
A
fluid retention
may lead to edema
17
Q
Imatinib is a potent inhibitor of __ and __
A
c-KIT, PDGFR
both RTKs
18
Q
Imatinib is a useful drug for the treatment of ___, where ~ 80% of tumors are driven by mutant c-KIT
A
GIST
19
Q
What should be performed regularly during the initial phase of imatinib therapy?
A
CBC
myelosuppression is a risk
20
Q
What causes resistance to imatinib?
A
point mutations in kinase domain
makes imatinib not effectively bind
newer BCR-ABL inhibitors are effective against many mutant
21
Q
Will imatinib effectively treat T315I mutation?
A
no
neither imatinib nor 2nd gen BDC-ABL inhibitors will treat
22
Q
What mutation is known as the “gatekeeper”?
A
T315I
23
Q
A highly resistant mutation in BCR-ABL known as the “gatekeeper” mutation is the result of a __ to __ point mutation at residue 315 (T315I)
A
threonine, isoleucine
24
Q
What metabolite can cause hepatotoxicity with dasatinib?
A
iminoquinone
25
What should be done regularly during initial phase of dasatinib therapy?
CBC
myelosuppression is a risk
26
Should nilotinib be taken with or without food?
take on empty stomach
avoid food 2 hours before and 1 hour after
27
What does nilotinib have a BBW for?
QT prolongation and sudden deaths
28
Does nilotinib bioavailability increase or decrease with food?
increases
should be taken on empty stomach
29
When given with a high fat meal, the Cmax and AUC of bosutinib increased __ and __ fold respectively
1.8, 1.7
30
Should bosutinib be taken with or without food?
with food
31
What is a risk with bosutinib therapy?
myelosuppression
CBC should be done regularly during initial phase of therapy
32
Activating mutations of EGFR are found in certain types of what cancers?
NSCLCs
33
30% of breast cancers overexpress __ due to gene amplification
HER2
34
Erlotinib is a potent inhibitor of __.
EGFR
35
What group in lapatinib gives it potent activity at HER2?
3-fluorobenzyl
36
The 3-fluorobenzyl ether of lapatinib gives it potent activity at __ in addition to its EGFR activity
HER2
37
What two AEs are caused by both erlotinib and lapatinib?
diarrhea
| acneiform skin rash
38
What mutation causes resistance to erlotinib?
T790M
39
__ accelerates the metabolic clearance of erlotinib by 24%
smoking
40
Should erlotinib be taken with or without food?
without
increases bioavailability to 100% and can cause toxicity
41
Erlotinib is used to treat what type of cancer?
NSCLC
42
Drugs that cause sustained increases in gastric pH __ mean exposure of erlotinib by 50%
a. increase
b. decrease
b. decrease
43
What drug can be used to treat pts with the T790M mutant EGFR?
osimertinib
preferred over erlotinib for pts with eGFR activating mutations
44
There is a risk for what two fatal conditions with osimertinib?
- interstitial lung disease/pneumonitis
- QT prolongation
pts with these Sx must d/c the drug
45
Should lapatinib be taken with or without food?
without
take one hour before or one hour after a meal
46
What effect will a high fat meal have on lapatinib?
increase exposure by 3 fold
take one hour before or one hour after a meal
47
How should lapatinib be taken with food?
one hour before or after
48
lapatinib and erlotinib are metabolized to what highly reactive products that cause toxicity?
iminoquinone
49
Erlotinib is associated with what potentially fatal disease?
interstitial lung disease
50
Both erlotinib and lapatinib are associated with what potentially fatal condition?
hepatotoxicity
lapatinib has BBW
51
4 toxicities associated with VEGFR2 inhibitors:
- bleeding
- HTN
- rare arterial thromboembolisms
- embryo/fetal toxicity
52
Which VEGFR2 inhibitor can cause yellow skin/body fluids?
sunitinib
53
Sunitinib has a BBW for what?
severe/fatal hepatotoxicity
54
Which VEGFR2 inhibitor should be taken with a low-fat meal?
regorafenib
55
Regorafenib should be taken with low fat meal < __ calories and < __ % fat
600, 30
56
The VEGFR2 inhibitor regorafenib has a BBW for what?
severe/fatal hepatotoxicity
57
The VEGFR2 inhibitor pazopanib has a BBW for what?
severe/fatal hepatotoxicity
58
What is the plasma half life of the VEGFR2 inhibitor axitinib?
2.5 to 6.1 hours
dosed twice daily
59
Which VEGFR2 inhibitor also inhibits c-MET?
cabozantinib
60
Abnormal activation of what protocol-oncogene is linked to proliferation, invasion, metastasis, and angiogenesis?
c-MET
cabozantinib inhibits this
61
What mutations are associated with 505 of melanoma tumors?
BRAF V600E
62
What should be combined with a BRAF inhibitor?
MEK inhibitor
BRAF and MEK inhibitors should be used together to delay resistance
63
What cancer occurs in 25% of pts on vemurafenib and/or dabrafenib therapy?
squamous cell carcinoma (SCC)
64
Drugs that raise gastric pH may reduce bioavailability of what BRAF inhibitor?
dabrafenib
65
Trametinib is used in combo with which BRAF inhibitor in V600E melanoma?
dabrafenib
66
Should trametinib be taken with or without food?
without
food reduces AUC and Cmax
67
Cobimetinib is used in combo with which BRAF inhibitor in V600E melanoma?
vemurafenib
68
What effect do high fat meals and PPIs have on cobimetinib exposure?
none
69
Which MEK inhibitor is not effected by high fat meals and PPIs?
cobimetinib
70
Multiple oncogenic signals in HR+ breast cancer come together to promote expression of __, which complexes with CDK4 and CDK6, and drives breast-cancer proliferation
cyclin D
71
Which type of inhibitors are used in HR+, HER2 negative breast cancer in conjunction with aromatase inhibitors or fulvestrant?
CDK4/CDK6 inhibitors
palbociclib, ribociclib, abemaciclib
72
What is a common AE of the CDK4/CDK6 inhibitors?
neutropenia
CBC should be monitored during therapy
73
An inversion on what chromosome results in production of EML4-ALK fusion RTK protein?
2p
74
EML4-ALK was determined to constitute 4-5% of all patients what cancer?
NSCL
75
Which EML4-ALK inhibitor was approved in 2013?
crizotinib
76
Which EML4-ALK inhibitor was approved in 2015?
alectinib
77
Activating mutations in what kinase can lead to B-cell lymphomas and leukemias?
BTK
78
The BTK inhibitor ibrutinib works by irreversible inhibition of what group?
alpha beta unsaturated amide
inhibits the "warhead"
79
What drug is a PI3K inhibitor?
idelalisib
80
The PI3K inhibitor idelalisib is approved for what two cancers?
CLL and certain NHLs
81
The PI3K inhibitor idelalisib has a BBW for what?
fatal toxicities
hepatic, severe diarrhea, colitis, pneumoniotis, interstitial perforation
82
__ has a BBW for fatal toxicities such as hepatic, severe diarrhea, colitis, pneumonitis, and intestinal perforation
idelalisib
83
Which drug is a FLT3 inhibitor ?
midostaurin
84
Activating mutations of which RTK are associated with 1/3 of adult AML pts?
FLT3
85
Should midostaurin be taken with or without food?
twice daily with food
exposure increases and Cmax decreases when taken with a meal
86
__ is a cytoplasmic serine‒threonine kinase and another component of the PI3K/AKT signaling pathway
mTOR
87
Temsirolimus and everolimus have substituents at what carbon that enhance solubility?
C40
semi-synthetic derivatives
88
Which mTOR is given weekly using IV infusions?
temsirolimus
89
Which mTOR is dosed daily via the oral route?
everolimus
90
Temsirolimus and everolimus increase the risk of what?
infection
delay wound healing
91
What degrades IκB, releasing NF-κB, which enters the nucleus and activates transcription of a numbers of genes?
26S proteasome
92
__ is highly expressed in many tumors and a key driver of tumor cell survival
NF-kB
93
Which 26S proteasome inhibitor has a unique boronic acid functional group essential for its activity ?
bortezomib
essential to its activity
94
Bortezomib reaches 60% proteasome inhibition within what time?
one hour
plasma half life is 5.5 hours, but proteasome inhibition half life is about 24 hours
95
Which 26S proteasome inhibitor has the AEs of thrombocytopenia, neutropenia, and peripheral neuropathy?
bortezomib
96
Which 26S proteasome inhibitor is the product of a prodrug?
ixazomib
ixazomib citrate > ixazomib
97
Should ixazomib be taken with or without food?
without
take at least one hour before or at least two hours after
98
Which 26S proteasome inhibitor has AEs of thrombocytopenia, peripheral neuropathy, and GI effects?
ixazomib
99
__ double mutation is embryonic lethal
BRCA
if only one defective parental copy, at risk for cancer development
100
Tumors deficient un BRCA1 or BRCA2 are sensitive to __ inhibition
PARP
normal cells and tumor cells with functioning BRCA proteins are not effected by PARP inhibition
101
The new PARP inhibitors olaparib and niraparib are approved for use in BRCA mutates types of what two cancers?
ovarian
| breast
102
The PARP inhibitors olaparib and niraparib have small but significant risk for what syndrome/cancer?
MDS/AML
myelodysplastic syndrome/acute myeloid leukemia
103
Pts on the PARP inhibitors olaparib or niraparib should be monitored for what toxicity?
hematological
should be d/c if MDS/AML is confirmed
104
Which drug is a BcI-2 inhibitor?
venetoclax
discovered via fragment based drug discovery approach
105
Over expression of the BcI-2 protein has what function?
anti-apoptotic
106
The __enhancer is very active in B-cells, which leads to overexpression of the Bcl-2 protein, which has an anti-apoptotic function
IgH
107
Pts on the BcI-2 inhibitor venetoclax should be premedicated with what?
anti-hyperuricemics
and adequately hydrated
108
What is a serious risk of the BcI-2 inhibitor venetoclax?
tumor lysis syndrome (TLS)
can lead to fatalities or renal failure
premedicate with anti-hyperuricemics and adequately hydrate
109
Venetoclax dose reductions are required to what type of strong-moderate inhibitors?
CYP3A
P-gp
can increase exposure
110
What drug is a HDAC inhibitor?
panobinostat
111
The HDAC inhibitor panobinostat is used to treat what type of cancer?
multiple myeloma
112
Panobinostat contains what type of acid?
hydroxamic acid
113
The HDAC inhibitor panobinostat has a BBW for what two things?
severe diarrhea, fatal cardiac events
treat with loperamide or d/c therapy
114
What should be obtained at baseline and periodically with panobinostat therapy?
ECG and electrolytes
115
What drug was used in the 1950s/60s as an antiemetic/sedative and caused severe birth defects in European children?
thalidomide
116
Which class of kinase inhibitor can only be dispensed by pharmacies via a REMS program?
IMiDs
thalidomide, lenalidomide, pamalidomide
117
The IMiDs thalidomide, lenalidomide, and pamalidomide have a BBW for increased risk of what?
thromboembolism
also embryo/fetal toxicity
118
3 dose limiting effects of thalidomide?
sedation
constipation
peripheral neuropathy
