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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
Erlotinib vs Lapatinib MOA?
Both of EGFR inhibitors, but Lapatinib inhibits HER2 due to the 3-flurobenzyl ether
26
Erlotinib and Lapatinib AE?
Diarrhea + Acneiform skin rash
27
Erlotinib vs Lapatinib Which one should be taken with food?
Neither; lapatinib should be taken 1 hr before or after
28
Erlotinib vs Lapatinib Which one is associated with fatal interstitial lung disease?
Erlotinib
29
Erlotinib vs Lapatinib Which one is associated w/ hepatotoxicity?
Both Lapatinib has a BBW of this
30
Erlotinib vs Lapatinib Which one has resistance to it?
Erlotinib T790M mutation
31
Erlotinib vs Lapatinib Which one is affected by pH?
Erlotinib Increased pH reduces drug exposure
32
Erlotinib vs Lapatinib Which one are metabolized to iminoquinone products?
Both, causes toxicity
33
Erlotinib vs Lapatinib Which one is affected by smoking?
Erlotinib Accelerates clearance of Rx
34
What is used to treat that T790M mutation that erlotinib cant treat?
Osimertinib
35
Osimertinib AE?
Fatal interstitial lung disease/pneumonitis and QT prolongation D/c drug if pt experiences this
36
What is a critical enzyme in angiogenesis that cancer cells secrete?
VEGFR2
37
VEGFR2 inhibitor AE?
Bleed, HTN, embolism, embryo/fetal toxicity
38
Sunitinib (Sutent) AE?
Yellowing in skin and fluids BBW of hepatotoxicity
39
How should you take Regorafenib?
Take w/ low fat meal
40
Regorafenib AE?
BBW of hepatotoxicity
41
Pazopanib AE?
BBW of hepatotoxicity
42
Axitinib info?
Short half life, dosed twice daily
43
Cabozantinib MOA?
Besides being a VEGFR2 inhibitor, it also inhibits c-MET (a proto-oncogene)
44
What kind of mutation is associated w/ 50% of melanoma tumors?
BRAF (V600E)
45
What is added on to BRAF inhibitors to help delay drug resistance?
MEK inhibitors
46
New squamous cell carcinoma now occurs in ____ of patients
25%
47
How does pH affect dabrafenib?
Coadmin of drugs that raise it reduces its solubility of dabrafenib and reduces its bioavailability
48
What drug is used in combo with vemurafenib? Dabrafenib?
Vemurafenib + Cobimetinib Dabrafenib + Trametinib both for V600E melanoma
49
Trametinib vs Cobimetinib Which one is affected by food?
Trametinib; take on an empty stomach
50
What signals drive breast cancer proliferation?
Through cyclin D (CDK4 and CDK6)
51
What are the CDK4/6 inhibitors and when are they used?
"..ciclib" HR+, HER2- with aromatase inhibitors or fulvestrant
52
CDK4/6 AE?
Neutropenia
53
What kind of chromosomal issue involves the production of EML4-ALK?
Inversion of chromosome 2p
54
What does EML4-ALK contribute to?
4-5% of all NSCLC cases
55
What are the EML4-ALK inhibitors?
Crizotinib + Alectinib
56
What does BTK contribute to ?
Lymphomas and leukemias
57
What are the BTK inhibitors?
Ibrutinib; IRREVERSIBLY inhibits the alpha, beta-unsaturated amide
58
What are the PI3K-delta inhibitors for?
CLL and NHLs
59
What are the PI3K-delta inhibitors?
Idelalisib
60
What do FLT3s contribute to?
1/3 of adult AML
61
What are the FLT3 inhibitors?
Midostaurin
62
Should Midostaurin be taken with food?
Yes, take twice daily
63
Where does mTOR play in?
Serine-Threonine kinase that plays in PI3K/AKT signaling pathway
64
Which carbon is substituted and what is its purpose in mTOR inhibitors?
C40, enhances solubility
65
What are the mTOR inhibitors and what is the R group?
Sirolimus; H Temsirolimus; two alcohols and a ketone Everolimus; one alcohol
66
Temsirolimus vs Everolimus Which one is given IV vs oral
Temsirolimus - IV Everolimus - PO
67
Temsirolimus + Everolimus AE?
Increased risk of infection and delayed wound healing
68
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 ```
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
abemaciclib (Verzenio®) axitinib (Inlyta®) crizotinib (Xalkori®) ibrutinib (Imbruvica®) vemurafenib (Zelboraf®) ``` B-cell lymphoma breast cancer melanoma NSCLC renal cell carcinoma (RCC) ```
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
What degrades IkB to release NF-kB? what is the significance?
26S proteosome Expressed in many tumors
71
Which drugs are proteasome inhibitors? What functional group contributes the work?
Bortezomib + Ixazomib; boronic acid functional group
72
Bortezomib AE?
Thrombocytopenia, neutropenia, peripheral neuropathy
73
Bortezomib half life info?
Short, reaches 60% within one hour of dosing with half life of 24 hrs
74
Ixazomib info and food?
Prodrug; allows oral dosing Take one hr before or 2 hrs after food
75
Ixazomib AE?
GI effects, thrombocytopenia, peripheral neuropathy
76
BRCA1 mutation info?
Double mutation is lethal Even one mutation is at an increased risk
77
Which class of drugs are useful for BRCA1/2 deficiency?
PARP inhibitors (Olaparib + Niraparib) for ovarian and breast cancer
78
Olaparib and Niraparib AE?
MDS, AML, d/c if confirmed
79
Venetoclax MOA?
Bcl-2 inhibitor; found via fragment-based drug discovery
80
What is active in B cells which leads to an overexpression of Bcl-2 proteins?
IgH enhancer
81
Venetoclax AE?
Tumor lysis syndrome; premedicate w/ antihyperuricemics and hydration Dont mix with CYP3A or P-gp inhibitors
82
Panobinostat MOA?
HDAC inhibitor
83
Panobinostat use?
Multiple myelomas
84
Panobinostat AE?
BBW of severe diarrhea (tx w/ loperamide) + cardiac events
85
Thalidomide use in the 50/60s?
Antiemetic and sedative leading to 10K birth defects
86
Thalidomide AE?
Sediaton, constipation, peripheral neuropathy BBW of thromboembolism
87
Thalidomide restrictions?
REMS program Childbearing age if no alternatives exist and must be on contraceptives
88
Protein kinases are enzymes that phosphorylate other proteins. True False
True
89
The vast majority of kinase inhibitors bind irreversibly to the ATP-binding site. True False
False
90
Receptor kinases are transmembrane proteins, having an intracellular and an extracellular domain. True False
True
91
Cytoplasmic (non-receptor kinases) are located outside the cell. True False
False
92
Abnormal activation of kinases arises from a single type of genetic change. True False
False
93
Kinases can be classified as tyrosine kinases (TK) or serine-threonine kinases (STK). True False
True
94
Less than twenty percent of small molecule kinase inhibitors have a MW ≥ 450 and cLogP ≥ 3.0. True False
False
95
Kinase inhibitors are typically metabolized by CYP450s with CYP3A4 often playing a prominent role. True False
True

IPT: Hem/Onc/Transplant (7 decks)

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