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IPT: Hem/Onc/Transplant > More Block 1 > Flashcards

More Block 1 Flashcards

1
Q

What are the types of protein kinases? What are they further divided into?

A

Tyrosine + Serine-Threonine kinases

Receptor kinases and Cytoplasmic (non receptor) kinases)

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2
Q

Where are cytoplasmic kinases located?

A

INSIDE the cell

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3
Q

What kind of proteins are receptor kinases?

A

Transmembrane proteins

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4
Q

What is found intracellularly and extracellularly in receptor kinases?

A

Intracellular domain = where ATP binds

Extracellular domain = ligand binding domain

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5
Q

Activation of kinases arises from what?

A

Abnormal activation arises from multiple types of genetic changes

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6
Q

Most (56 of 62) kinase inhibitors target what?

A

They COMPETITIVELY target ATP binding sites

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7
Q

What connects kinase inhibitors to the hinge region (adenine pocket) of the ATP binding pocket?

A

Kinase inhibitors have H-bond acceptors and donors that connect to them

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8
Q

What is the pharmacophore for irreversible kinase inhibitors?

A

alpha, beta unsaturated AMIDE

carbons with ketone and NH

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9
Q

Kinase inhibitors vs orally available drug classes, which one has a higher molecular weight? Lipophilic?

A

Kinase inhibitors for both

Lipophilic = high protein binding ability

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10
Q

(T/F)

Kinase inhibitors are typically metabolized by CYP450

A

True

Mostly with CYP3A4

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11
Q

Kinase inhibitor general issues?

A

QT interval prolongation

Embryo/fetal toxicity

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12
Q

Protein kinases are enzymes that ________ other proteins.

A

phosphorylate

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13
Q

What causes most adult CML?

A

Aberrant Philadelphia chromosome; reciprocal translocation between chromo 9 and 22

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14
Q

Imatinib MOA?

A

Inhibits BCR-ABL

Inhibits c-KIT and PDGFR

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15
Q

Imatinib AE?

A

Edema + Myelosuppression (do regular CBC)

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16
Q

What causes resistance to Imatinib? What can use you to treat it?

A

Point mutation that imatinib does not bind to

Use BCR-ABL inhibitors that came after it

Bosutinib
Nilotinib
Dasatanib

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17
Q

What something that imatinib nor the second gen BCR-ABL inhibitors CAN’T treat?

A

Cancer cells w/ T315I mutation

Its a gatekeeper mutation as a result of a threonine to isoleucine point mutation

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18
Q

Dasatinib AE?

A

Myelosuppression

Hepatotoxicity (due to hydroxylation of phenyl ring that generates an iminoquinone metabolite)

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19
Q

Nilotinib AE?

A

Myelosuppression

BBW of QT prolongation and sudden death

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20
Q

How should pt take Nilotinib?

A

Take on empty stomach, avoid food 2 hrs before and 1 hr after food

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21
Q

How should pt take Bosutinib?

A

Take with high fat meal

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22
Q

Bosutinib AE?

A

Myelosuppression

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23
Q

What is mutated in certain NSCLCs?

A

Activating mutations of EGFR; Erlotinib is used this treat it

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24
Q

Gene amplification of ____ cause 30% of breast cancers

A

HER2

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25
Q

Erlotinib vs Lapatinib MOA?

A

Both of EGFR inhibitors, but Lapatinib inhibits HER2 due to the 3-flurobenzyl ether

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26
Q

Erlotinib and Lapatinib AE?

A

Diarrhea + Acneiform skin rash

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27
Q

Erlotinib vs Lapatinib

Which one should be taken with food?

A

Neither; lapatinib should be taken 1 hr before or after

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28
Q

Erlotinib vs Lapatinib

Which one is associated with fatal interstitial lung disease?

A

Erlotinib

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29
Q

Erlotinib vs Lapatinib

Which one is associated w/ hepatotoxicity?

A

Both

Lapatinib has a BBW of this

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30
Q

Erlotinib vs Lapatinib

Which one has resistance to it?

A

Erlotinib

T790M mutation

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31
Q

Erlotinib vs Lapatinib

Which one is affected by pH?

A

Erlotinib

Increased pH reduces drug exposure

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32
Q

Erlotinib vs Lapatinib

Which one are metabolized to iminoquinone products?

A

Both, causes toxicity

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33
Q

Erlotinib vs Lapatinib

Which one is affected by smoking?

A

Erlotinib

Accelerates clearance of Rx

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34
Q

What is used to treat that T790M mutation that erlotinib cant treat?

A

Osimertinib

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35
Q

Osimertinib AE?

A

Fatal interstitial lung disease/pneumonitis and QT prolongation

D/c drug if pt experiences this

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36
Q

What is a critical enzyme in angiogenesis that cancer cells secrete?

A

VEGFR2

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37
Q

VEGFR2 inhibitor AE?

A

Bleed, HTN, embolism, embryo/fetal toxicity

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38
Q

Sunitinib (Sutent) AE?

A

Yellowing in skin and fluids

BBW of hepatotoxicity

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39
Q

How should you take Regorafenib?

A

Take w/ low fat meal

40
Q

Regorafenib AE?

A

BBW of hepatotoxicity

41
Q

Pazopanib AE?

A

BBW of hepatotoxicity

42
Q

Axitinib info?

A

Short half life, dosed twice daily

43
Q

Cabozantinib MOA?

A

Besides being a VEGFR2 inhibitor, it also inhibits c-MET (a proto-oncogene)

44
Q

What kind of mutation is associated w/ 50% of melanoma tumors?

A

BRAF (V600E)

45
Q

What is added on to BRAF inhibitors to help delay drug resistance?

A

MEK inhibitors

46
Q

New squamous cell carcinoma now occurs in ____ of patients

A

25%

47
Q

How does pH affect dabrafenib?

A

Coadmin of drugs that raise it reduces its solubility of dabrafenib and reduces its bioavailability

48
Q

What drug is used in combo with vemurafenib? Dabrafenib?

A

Vemurafenib + Cobimetinib

Dabrafenib + Trametinib

both for V600E melanoma

49
Q

Trametinib vs Cobimetinib

Which one is affected by food?

A

Trametinib; take on an empty stomach

50
Q

What signals drive breast cancer proliferation?

A

Through cyclin D (CDK4 and CDK6)

51
Q

What are the CDK4/6 inhibitors and when are they used?

A

”..ciclib”

HR+, HER2- with aromatase inhibitors or fulvestrant

52
Q

CDK4/6 AE?

A

Neutropenia

53
Q

What kind of chromosomal issue involves the production of EML4-ALK?

A

Inversion of chromosome 2p

54
Q

What does EML4-ALK contribute to?

A

4-5% of all NSCLC cases

55
Q

What are the EML4-ALK inhibitors?

A

Crizotinib + Alectinib

56
Q

What does BTK contribute to ?

A

Lymphomas and leukemias

57
Q

What are the BTK inhibitors?

A

Ibrutinib; IRREVERSIBLY inhibits the alpha, beta-unsaturated amide

58
Q

What are the PI3K-delta inhibitors for?

A

CLL and NHLs

59
Q

What are the PI3K-delta inhibitors?

A

Idelalisib

60
Q

What do FLT3s contribute to?

A

1/3 of adult AML

61
Q

What are the FLT3 inhibitors?

A

Midostaurin

62
Q

Should Midostaurin be taken with food?

A

Yes, take twice daily

63
Q

Where does mTOR play in?

A

Serine-Threonine kinase that plays in PI3K/AKT signaling pathway

64
Q

Which carbon is substituted and what is its purpose in mTOR inhibitors?

A

C40, enhances solubility

65
Q

What are the mTOR inhibitors and what is the R group?

A

Sirolimus; H

Temsirolimus; two alcohols and a ketone

Everolimus; one alcohol

66
Q

Temsirolimus vs Everolimus

Which one is given IV vs oral

A

Temsirolimus - IV

Everolimus - PO

67
Q

Temsirolimus + Everolimus AE?

A

Increased risk of infection and delayed wound healing

68
Q

crizotinib (Xalkori®)

dabrafenib (Tafinlar®)

ibrutinib (Imbruvica®)

idelalisib (Zydelig®)

palbociclib (Ibrance®)

pazopanib (Votrient®)

trametinib (Mekinist®)

BRAF V600E
BTK
CDK4/CDK6
EML4-ALK
MEK
PI3K-δ
VEGFR2
A

trametinib (Mekinist®)
MEK

crizotinib (Xalkori®)
EML4-ALK

dabrafenib (Tafinlar®)
BRAF V600E

idelalisib (Zydelig®)
PI3K-δ

palbociclib (Ibrance®)
CDK4/CDK6

pazopanib (Votrient®)
VEGFR2

ibrutinib (Imbruvica®)
BTK

69
Q

abemaciclib (Verzenio®)

axitinib (Inlyta®)

crizotinib (Xalkori®)

ibrutinib (Imbruvica®)

vemurafenib (Zelboraf®)

B-cell lymphoma
breast cancer
melanoma
NSCLC
renal cell carcinoma (RCC)
A

crizotinib (Xalkori®)
non-small cell lung cancer (NSCLC)

abemaciclib (Verzenio®)
breast cancer

vemurafenib (Zelboraf®)
melanoma

ibrutinib (Imbruvica®)
B-cell lymphoma

axitinib (Inlyta®)
renal cell carcinoma (RCC)

70
Q

What degrades IkB to release NF-kB? what is the significance?

A

26S proteosome

Expressed in many tumors

71
Q

Which drugs are proteasome inhibitors? What functional group contributes the work?

A

Bortezomib + Ixazomib; boronic acid functional group

72
Q

Bortezomib AE?

A

Thrombocytopenia, neutropenia, peripheral neuropathy

73
Q

Bortezomib half life info?

A

Short, reaches 60% within one hour of dosing with half life of 24 hrs

74
Q

Ixazomib info and food?

A

Prodrug; allows oral dosing

Take one hr before or 2 hrs after food

75
Q

Ixazomib AE?

A

GI effects, thrombocytopenia, peripheral neuropathy

76
Q

BRCA1 mutation info?

A

Double mutation is lethal

Even one mutation is at an increased risk

77
Q

Which class of drugs are useful for BRCA1/2 deficiency?

A

PARP inhibitors (Olaparib + Niraparib) for ovarian and breast cancer

78
Q

Olaparib and Niraparib AE?

A

MDS, AML, d/c if confirmed

79
Q

Venetoclax MOA?

A

Bcl-2 inhibitor; found via fragment-based drug discovery

80
Q

What is active in B cells which leads to an overexpression of Bcl-2 proteins?

A

IgH enhancer

81
Q

Venetoclax AE?

A

Tumor lysis syndrome; premedicate w/ antihyperuricemics and hydration

Dont mix with CYP3A or P-gp inhibitors

82
Q

Panobinostat MOA?

A

HDAC inhibitor

83
Q

Panobinostat use?

A

Multiple myelomas

84
Q

Panobinostat AE?

A

BBW of severe diarrhea (tx w/ loperamide) + cardiac events

85
Q

Thalidomide use in the 50/60s?

A

Antiemetic and sedative leading to 10K birth defects

86
Q

Thalidomide AE?

A

Sediaton, constipation, peripheral neuropathy

BBW of thromboembolism

87
Q

Thalidomide restrictions?

A

REMS program

Childbearing age if no alternatives exist and must be on contraceptives

88
Q

Protein kinases are enzymes that phosphorylate other proteins.

True
False

A

True

89
Q

The vast majority of kinase inhibitors bind irreversibly to the ATP-binding site.

True
False

A

False

90
Q

Receptor kinases are transmembrane proteins, having an intracellular and an extracellular domain.

True
False

A

True

91
Q

Cytoplasmic (non-receptor kinases) are located outside the cell.

True
False

A

False

92
Q

Abnormal activation of kinases arises from a single type of genetic change.

True
False

A

False

93
Q

Kinases can be classified as tyrosine kinases (TK) or serine-threonine kinases (STK).

True
False

A

True

94
Q

Less than twenty percent of small molecule kinase inhibitors have a MW ≥ 450 and cLogP ≥ 3.0.

True
False

A

False

95
Q

Kinase inhibitors are typically metabolized by CYP450s with CYP3A4 often playing a prominent role.

True
False

A

True

IPT: Hem/Onc/Transplant (7 decks)

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