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7361 Hem/Onc Block 1 > Kinase Inhibitors > Flashcards

Kinase Inhibitors Flashcards

1
Q

2 types of protein kinases?

A

tyrosine kinases

serine-threonine kinases

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2
Q

Where are cytoplasmic (non-receptor kinases) located?

A

inside the cell

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3
Q

Are receptor kinases transmembrane proteins?

A

yes - have intracellular domain and extracellular (ligand binding domain)

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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

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5
Q

The vast majority of kinase inhibitors ___ target the ATP binding site.

a. competitively
b. non-competitively

A

a. competitively

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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

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7
Q

What is the pharmacophore, or “warhead” for irreversible kinase inhibitors?

A

alpha beta unsaturated amide

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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

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9
Q

Do small molecule kinase inhibitors have high or low protein binding?

A

high protein binding

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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

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11
Q

Many kinase inhibitors have what AE?

A

QT interval prolongation

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12
Q

What CYP often plays a role in kinase metabolism?

A

3A4

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13
Q

The Philadelphia chromosome is caused by a reciprocal translocation between what chromosomes?

A

9 and 22

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14
Q

What is the cause of > 90% of chronic myelogenous leukemia (CML)?

A

Philadelphia chromosome

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15
Q

What is target of imatinib?

A

BCR-ABL

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16
Q

What can imatinib promote?

A

fluid retention

may lead to edema

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17
Q

Imatinib is a potent inhibitor of __ and __

A

c-KIT, PDGFR

both RTKs

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18
Q

Imatinib is a useful drug for the treatment of ___, where ~ 80% of tumors are driven by mutant c-KIT

A

GIST

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19
Q

What should be performed regularly during the initial phase of imatinib therapy?

A

CBC

myelosuppression is a risk

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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

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21
Q

Will imatinib effectively treat T315I mutation?

A

no

neither imatinib nor 2nd gen BDC-ABL inhibitors will treat

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22
Q

What mutation is known as the “gatekeeper”?

A

T315I

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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

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24
Q

What metabolite can cause hepatotoxicity with dasatinib?

A

iminoquinone

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25
Q

What should be done regularly during initial phase of dasatinib therapy?

A

CBC

myelosuppression is a risk

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26
Q

Should nilotinib be taken with or without food?

A

take on empty stomach

avoid food 2 hours before and 1 hour after

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27
Q

What does nilotinib have a BBW for?

A

QT prolongation and sudden deaths

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28
Q

Does nilotinib bioavailability increase or decrease with food?

A

increases

should be taken on empty stomach

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29
Q

When given with a high fat meal, the Cmax and AUC of bosutinib increased __ and __ fold respectively

A

1.8, 1.7

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30
Q

Should bosutinib be taken with or without food?

A

with food

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31
Q

What is a risk with bosutinib therapy?

A

myelosuppression

CBC should be done regularly during initial phase of therapy

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32
Q

Activating mutations of EGFR are found in certain types of what cancers?

A

NSCLCs

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33
Q

30% of breast cancers overexpress __ due to gene amplification

A

HER2

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34
Q

Erlotinib is a potent inhibitor of __.

A

EGFR

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35
Q

What group in lapatinib gives it potent activity at HER2?

A

3-fluorobenzyl

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36
Q

The 3-fluorobenzyl ether of lapatinib gives it potent activity at __ in addition to its EGFR activity

A

HER2

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37
Q

What two AEs are caused by both erlotinib and lapatinib?

A

diarrhea

acneiform skin rash

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38
Q

What mutation causes resistance to erlotinib?

A

T790M

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39
Q

__ accelerates the metabolic clearance of erlotinib by 24%

A

smoking

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40
Q

Should erlotinib be taken with or without food?

A

without

increases bioavailability to 100% and can cause toxicity

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41
Q

Erlotinib is used to treat what type of cancer?

A

NSCLC

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42
Q

Drugs that cause sustained increases in gastric pH __ mean exposure of erlotinib by 50%

a. increase
b. decrease

A

b. decrease

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43
Q

What drug can be used to treat pts with the T790M mutant EGFR?

A

osimertinib

preferred over erlotinib for pts with eGFR activating mutations

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44
Q

There is a risk for what two fatal conditions with osimertinib?

A
  • interstitial lung disease/pneumonitis
  • QT prolongation

pts with these Sx must d/c the drug

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45
Q

Should lapatinib be taken with or without food?

A

without

take one hour before or one hour after a meal

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46
Q

What effect will a high fat meal have on lapatinib?

A

increase exposure by 3 fold

take one hour before or one hour after a meal

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47
Q

How should lapatinib be taken with food?

A

one hour before or after

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48
Q

lapatinib and erlotinib are metabolized to what highly reactive products that cause toxicity?

A

iminoquinone

49
Q

Erlotinib is associated with what potentially fatal disease?

A

interstitial lung disease

50
Q

Both erlotinib and lapatinib are associated with what potentially fatal condition?

A

hepatotoxicity

lapatinib has BBW

51
Q

4 toxicities associated with VEGFR2 inhibitors:

A
  • bleeding
  • HTN
  • rare arterial thromboembolisms
  • embryo/fetal toxicity
52
Q

Which VEGFR2 inhibitor can cause yellow skin/body fluids?

A

sunitinib

53
Q

Sunitinib has a BBW for what?

A

severe/fatal hepatotoxicity

54
Q

Which VEGFR2 inhibitor should be taken with a low-fat meal?

A

regorafenib

55
Q

Regorafenib should be taken with low fat meal < __ calories and < __ % fat

A

600, 30

56
Q

The VEGFR2 inhibitor regorafenib has a BBW for what?

A

severe/fatal hepatotoxicity

57
Q

The VEGFR2 inhibitor pazopanib has a BBW for what?

A

severe/fatal hepatotoxicity

58
Q

What is the plasma half life of the VEGFR2 inhibitor axitinib?

A

2.5 to 6.1 hours

dosed twice daily

59
Q

Which VEGFR2 inhibitor also inhibits c-MET?

A

cabozantinib

60
Q

Abnormal activation of what protocol-oncogene is linked to proliferation, invasion, metastasis, and angiogenesis?

A

c-MET

cabozantinib inhibits this

61
Q

What mutations are associated with 505 of melanoma tumors?

A

BRAF V600E

62
Q

What should be combined with a BRAF inhibitor?

A

MEK inhibitor

BRAF and MEK inhibitors should be used together to delay resistance

63
Q

What cancer occurs in 25% of pts on vemurafenib and/or dabrafenib therapy?

A

squamous cell carcinoma (SCC)

64
Q

Drugs that raise gastric pH may reduce bioavailability of what BRAF inhibitor?

A

dabrafenib

65
Q

Trametinib is used in combo with which BRAF inhibitor in V600E melanoma?

A

dabrafenib

66
Q

Should trametinib be taken with or without food?

A

without

food reduces AUC and Cmax

67
Q

Cobimetinib is used in combo with which BRAF inhibitor in V600E melanoma?

A

vemurafenib

68
Q

What effect do high fat meals and PPIs have on cobimetinib exposure?

A

none

69
Q

Which MEK inhibitor is not effected by high fat meals and PPIs?

A

cobimetinib

70
Q

Multiple oncogenic signals in HR+ breast cancer come together to promote expression of __, which complexes with CDK4 and CDK6, and drives breast-cancer proliferation

A

cyclin D

71
Q

Which type of inhibitors are used in HR+, HER2 negative breast cancer in conjunction with aromatase inhibitors or fulvestrant?

A

CDK4/CDK6 inhibitors

palbociclib, ribociclib, abemaciclib

72
Q

What is a common AE of the CDK4/CDK6 inhibitors?

A

neutropenia

CBC should be monitored during therapy

73
Q

An inversion on what chromosome results in production of EML4-ALK fusion RTK protein?

A

2p

74
Q

EML4-ALK was determined to constitute 4-5% of all patients what cancer?

A

NSCL

75
Q

Which EML4-ALK inhibitor was approved in 2013?

A

crizotinib

76
Q

Which EML4-ALK inhibitor was approved in 2015?

A

alectinib

77
Q

Activating mutations in what kinase can lead to B-cell lymphomas and leukemias?

A

BTK

78
Q

The BTK inhibitor ibrutinib works by irreversible inhibition of what group?

A

alpha beta unsaturated amide

inhibits the “warhead”

79
Q

What drug is a PI3K inhibitor?

A

idelalisib

80
Q

The PI3K inhibitor idelalisib is approved for what two cancers?

A

CLL and certain NHLs

81
Q

The PI3K inhibitor idelalisib has a BBW for what?

A

fatal toxicities

hepatic, severe diarrhea, colitis, pneumoniotis, interstitial perforation

82
Q

__ has a BBW for fatal toxicities such as hepatic, severe diarrhea, colitis, pneumonitis, and intestinal perforation

A

idelalisib

83
Q

Which drug is a FLT3 inhibitor ?

A

midostaurin

84
Q

Activating mutations of which RTK are associated with 1/3 of adult AML pts?

A

FLT3

85
Q

Should midostaurin be taken with or without food?

A

twice daily with food

exposure increases and Cmax decreases when taken with a meal

86
Q

__ is a cytoplasmic serine‒threonine kinase and another component of the PI3K/AKT signaling pathway

A

mTOR

87
Q

Temsirolimus and everolimus have substituents at what carbon that enhance solubility?

A

C40

semi-synthetic derivatives

88
Q

Which mTOR is given weekly using IV infusions?

A

temsirolimus

89
Q

Which mTOR is dosed daily via the oral route?

A

everolimus

90
Q

Temsirolimus and everolimus increase the risk of what?

A

infection

delay wound healing

91
Q

What degrades IκB, releasing NF-κB, which enters the nucleus and activates transcription of a numbers of genes?

A

26S proteasome

92
Q

__ is highly expressed in many tumors and a key driver of tumor cell survival

A

NF-kB

93
Q

Which 26S proteasome inhibitor has a unique boronic acid functional group essential for its activity ?

A

bortezomib

essential to its activity

94
Q

Bortezomib reaches 60% proteasome inhibition within what time?

A

one hour

plasma half life is 5.5 hours, but proteasome inhibition half life is about 24 hours

95
Q

Which 26S proteasome inhibitor has the AEs of thrombocytopenia, neutropenia, and peripheral neuropathy?

A

bortezomib

96
Q

Which 26S proteasome inhibitor is the product of a prodrug?

A

ixazomib

ixazomib citrate > ixazomib

97
Q

Should ixazomib be taken with or without food?

A

without

take at least one hour before or at least two hours after

98
Q

Which 26S proteasome inhibitor has AEs of thrombocytopenia, peripheral neuropathy, and GI effects?

A

ixazomib

99
Q

__ double mutation is embryonic lethal

A

BRCA

if only one defective parental copy, at risk for cancer development

100
Q

Tumors deficient un BRCA1 or BRCA2 are sensitive to __ inhibition

A

PARP

normal cells and tumor cells with functioning BRCA proteins are not effected by PARP inhibition

101
Q

The new PARP inhibitors olaparib and niraparib are approved for use in BRCA mutates types of what two cancers?

A

ovarian

breast

102
Q

The PARP inhibitors olaparib and niraparib have small but significant risk for what syndrome/cancer?

A

MDS/AML

myelodysplastic syndrome/acute myeloid leukemia

103
Q

Pts on the PARP inhibitors olaparib or niraparib should be monitored for what toxicity?

A

hematological

should be d/c if MDS/AML is confirmed

104
Q

Which drug is a BcI-2 inhibitor?

A

venetoclax

discovered via fragment based drug discovery approach

105
Q

Over expression of the BcI-2 protein has what function?

A

anti-apoptotic

106
Q

The __enhancer is very active in B-cells, which leads to overexpression of the Bcl-2 protein, which has an anti-apoptotic function

A

IgH

107
Q

Pts on the BcI-2 inhibitor venetoclax should be premedicated with what?

A

anti-hyperuricemics

and adequately hydrated

108
Q

What is a serious risk of the BcI-2 inhibitor venetoclax?

A

tumor lysis syndrome (TLS)

can lead to fatalities or renal failure

premedicate with anti-hyperuricemics and adequately hydrate

109
Q

Venetoclax dose reductions are required to what type of strong-moderate inhibitors?

A

CYP3A
P-gp

can increase exposure

110
Q

What drug is a HDAC inhibitor?

A

panobinostat

111
Q

The HDAC inhibitor panobinostat is used to treat what type of cancer?

A

multiple myeloma

112
Q

Panobinostat contains what type of acid?

A

hydroxamic acid

113
Q

The HDAC inhibitor panobinostat has a BBW for what two things?

A

severe diarrhea, fatal cardiac events

treat with loperamide or d/c therapy

114
Q

What should be obtained at baseline and periodically with panobinostat therapy?

A

ECG and electrolytes

115
Q

What drug was used in the 1950s/60s as an antiemetic/sedative and caused severe birth defects in European children?

A

thalidomide

116
Q

Which class of kinase inhibitor can only be dispensed by pharmacies via a REMS program?

A

IMiDs

thalidomide, lenalidomide, pamalidomide

117
Q

The IMiDs thalidomide, lenalidomide, and pamalidomide have a BBW for increased risk of what?

A

thromboembolism

also embryo/fetal toxicity

118
Q

3 dose limiting effects of thalidomide?

A

sedation
constipation
peripheral neuropathy

7361 Hem/Onc Block 1 (9 decks)

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