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PHRM 864 > L5-6 Kinases > Flashcards

L5-6 Kinases Flashcards

1
Q

what do all of the kinase inhibitors bind to?

A

the ATP-binding site of protein kinases

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2
Q

what AA is a common target of several kinases? (slide 19)

A

tyrosine

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3
Q

what 3 AAs can be phosphorylated and are substrates for kinases and why

A

Tyrosine
Serine
Threonine
they all have -OH group

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4
Q

what balances the activity of kinases by removing phosphates?

A

phosphatases - lol

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5
Q

what common step in cell signaling activates kinase activity?

A

dimerization of something somewhere idk

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6
Q

Types of kinase inhibitors:
Bind to active conformation of the kinase
A. Type I
B. Type II
C. Type III

A

A

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7
Q

Types of kinase inhibitors:
Bind and stabilize the inactive conformation of the kinase
A. Type I
B. Type II
C. Type III

A

B

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8
Q

Types of kinase inhibitors:
Occupy an allosteric pocket outside of the ATP-binding pocket
A. Type I
B. Type II
C. Type III

A

C

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9
Q

Competitive Inhibitors bind kinase in a ________ fashion and therefore must compete with _______ for binding.

A

reversible
ATP

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9
Q

What type of TKI is gefitinib?

A

Type I

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10
Q

where does gefitinib bind?

A

The ATP-binding site of the TK domain of EGFR

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11
Q

EGFR functions through what?

A

TK activity

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12
Q

EGFR signaling induces what?

A

cell proliferation

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13
Q

Erlotinib is a small molecule ________ inhibitor of EGFR tyrosine kinase

A

Reversible

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14
Q

T or F:
Erlotinib is a competitive inhibitor

A

True, inhibits the enzyme by binding to the ATP binding site in the kinase domain (of EGFR)

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15
Q

Inhibition of kinase activity turns off what?

A

the signal to proliferate

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16
Q

Gefitinib and Erlotinib are both approved for patients that fall under what criteria?

A

NSCLC
EGFR exon 19 or 21 mutations

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17
Q

3 common adverse effects of gefitinib and erlotinib

A

fatigue
rash
diarrhea

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18
Q

Afatinib is a ______ inhibitor of all ____ receptors

A

covalent**
ErbB

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19
Q

what is Afatinib approved for?

A

EGFR mutant NSCLC with EGFR mutations (exon 19 and 21)

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20
Q

What is dacomitinib approved for?

A

non-resistant EGFR mutant lung cancer

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21
Q

what is the main side effect “we should know” from EGFR inhibitors?

A

skin rash

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22
Q

what mutation causes resistance to gefitinib?

A

T790M **

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23
Q

Osimertinib:
- A ___ generation EGFR inhibitor
- ______ kinase inhibitor
- Effective against the ____ mutant EGFR

A

third
covalent
T790M

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24
Q

EGFR forms a heterodimer with ______

A

HER2 (ErbB2)

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25
Q

HER2 is genomically _____ in breast cancer

A

amplified

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26
Q

Lapatinib:
- small molecule TKI that blocks _____ and _____ signaling

A

HER2
EGFR

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27
Q

Lapatinib:
- selective for the treatment of _______ breast cancer

A

HER2+.

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28
Q

lapatinib:
- currently approved (in combination with capecitabine) for the treatment of ________ ________ breast cancer in pts who have progressed on other therapies

A

advanced metastatic (late stages)

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29
Q

T or F:
Lapatinib is an irreversible inhibitor of both EGFR and HER2

A

false, reversible

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30
Q

3 common side effects of lapatinib

A

diarrhea
nausea
vomiting
(also watch for sxs of congestive heart failure for some reason)

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31
Q

Tucatinib:
- small molecule TKI that preferentially binds ____

A

HER2

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32
Q

Tucatinib:
- selective for the tx of _______ ______

A

HER2+ breast cancer

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33
Q

lapatinib:
- currently approved (in combination with capecitabine and trastuzumab) for the treatment of ________ ________ breast cancer in pts who have progressed on other therapies

A

advanced metastatic (sorry same card twice kinda minus the trast drug)

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34
Q

Tucatinib has reduced adverse reactions compared to lapatinib, why is this?

A

since it is more selective for HER2

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35
Q

Which compounds inhibit EGFR?
A. Gefitinib
B. Osmertinib
C. Afatinib
D. Lapatinib
E. All of the above

A

E

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36
Q

What mutation in EGFR confers resistance to 1st and 2nd generation EGFR inhibitors?

A. L858R
B. Exon 19 deletion
C. Exon 14 deletion
D. T790M

A

D

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37
Q

what the fuck is the FLT3 (fms-like tyrosine kinase 3) ligand?

A

a cytokine receptor important for hematopoietic cell survival and proliferation

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38
Q

FLT3 mutations are found in 30% of what?

A

acute myeloid leukemia (AML)

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39
Q

Mutations in FLT3 lead to increased ______ and decreased______

A

proliferation
apoptosis

40
Q

1st gen FLT3 inhibitors (midostaurin) are broad ________ _______

A

kinase inhibitors, no wonder theyre in this deck huh

41
Q

2nd gen FLT3 inhibitors (crenolanib) are better than 1st gen, but why?

A

more specific

42
Q

Type II inhibitors (FLT3 specific) (e.g. Quizartinib) are specific for what? *

A

ITD (internal tandem duplication) mutations

43
Q

MET is the receptor for what?

A

hepatocyte growth factor (HGF)

44
Q

capmatinib is a _____ inhibitor

A

MET (my friend wears a METS baseball CAP?)

45
Q

In addition to directly driving tumor cell growth, Vascular Endothelial Growth Factor Receptor (VEGFR) is also critical to __________ __________making it an attractive target.

A

tumor angiogenesis

46
Q

if you see “Bcr-Abl” what should you instantly think about?

A

philadelphia

47
Q

Bcr-Abl:
_______ protein with TK activity

A

fusion

48
Q

Philadelphia chromosome (Ph1) is the prototype ___________ ____________

A

chromosomal translocation

49
Q

The Ph1 chromosome is demonstrable in ~95% of what type of cancer

A

chronic myeloid leukemia (CML)

50
Q

T or F:
Bcr-Abl is a chimeric protein

A

true i guess idk

51
Q

T or F:
Bcr-Abl is a crucial protein for apoptosis

A

False, it actually drives several proliferation pathways

52
Q

if you see Bcr-Abl, what type of cancer should you think of?

A

CML

53
Q

T or F:
Bcr-Abl acts as an overexpressed kinase

A

True (i think the Abl part is a TK)

54
Q

The kinase activity of the Bcr-Abl protein is _________ active. What does this mean?

A

Constitutively
constitutive activity results in malignancy **

55
Q

Imatinib is a Type ____ small molecule inhibitor of the Abl TK

A

Type II

56
Q

what does inhibiting the Abl TK result in? (2 things)

A

reduced proliferation and enhanced apoptosis in CML and GIST

57
Q

Imatinib primary indication

A

Treatment of CML
(IM A CHRONIC nib?)

58
Q

toxicities of imatinib

A

N/V
edema
neutropenia and thrombocytopenia

59
Q

so basically, if an exam question says anything about CML whats your next move?

A

clicking the shit that says Imatinib

60
Q

Ponatinib inhibits what?

A

Bcr-Abl, so both components instead of just the one?

61
Q

T or F:
Ponatinib is effective against ALL the major mutant forms of Bcr-Abl

A

True, actually

62
Q

Ponatinib can inhibit the “gatekeeper” ** mutation ______ that is resistant to all other Bcr-Abl compounds

A

T315

63
Q

okay here’s the scene. you’re sitting in the exam room. you click to question 33. It says something about T315. What do you do?

A

SMACK whatever option has Ponatinib

64
Q

EML4-ALK translocation is significant driver event in what?

A

lung cancer

65
Q

what is the ALK part of EML4-ALK?

A

something about wild type ALK. he is a transmembrane receptor TK similar to EGFR

66
Q

is EGFR a receptor tyrosine kinase (RTK) ?

A

yes

67
Q

When ALK becomes “inappropriately” fused with ELM4, what happens?

A

it becomes cytoplasmic and constitutively active (which is bad im pretty sure)

68
Q

What is the significance of ALK becoming cytoplasmic after fusing to ELM4?

A

it turns on pathways that ALK would not normally turn on

69
Q

Alectinib MOA-ish

A

more specific inhibitor of ALK

70
Q

T or F:
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase

A

True

71
Q

T or F:
Alectinib requires a companion diagnostic test for the fusion gene

A

true

72
Q

Indication of Alectinib

A

ALK+ NSCLC who have progressed on or are intolerant to crizotinib

73
Q

what other drug is an ALK inhibitor that isnt alectinib

A

Brigatinib

74
Q

when you see BRAF what cancer do you think of?

A

boobie

75
Q

Dabrafenib MOA

A

2nd gen BRAF-V600 inhibitor

76
Q

Dabrafenib approved in combo with _______ for tx of BRAF V600E/K-mutant metastatic melanoma

A

trametinib (I MET this guy and he DABbed me up)

77
Q

Valine(V) 600E/K is a mutation you see in what? what drug do you use when you see it?

A

melanoma
Dabrafenib

78
Q

Trametinib inhibits the kinase activity of ____ and _____

A

MEK1 and MEK2

79
Q

Trametinib has a limitation of use, what is it?

A

pts who have received prior BRAF inhibitor therapy

80
Q

3 most common AE’s for trametinib

A

Rash*
diarrhea
lymphedema.

81
Q

Which type of inhibitor is Trametinib?
A. 1st gen (active site)
B. 2nd gen
C. 3rd gen (allosteric site)

A

C. allosteric

82
Q

Encorafenib and Binimetinib (very niche on slide 59) can both be used in combo for pts with what?

A

UNRESECTABLE or metastatic melanoma with a BRAF V600E. or V600K mutation

83
Q

Brutons TK (BTK) is important for normal __ cell activity and __ cell tumor growth

A

B and B

84
Q

Ibrutinib is a covalent inhibitor of ?

A

BTK (brutons TK) (woah brut is in the name!)

85
Q

BTK is commonly associated with what?

A

sorry this is vague but its B-cell malignancies

86
Q

BTK inhibitors are used primarily in which 2 cancers

A

mantle cell lymphoma (MCL)
chronic lymphocytic leukemia (CLL)

87
Q

2nd gen BTK inhibitor:
A. Ibrutinib
B. Acalabrutinib

A

B

88
Q

T or F:
Both ibrutinib and acalabrutinib are covalent BTK inhibitors

A

True

89
Q

what is acalabrutinib indicated for?

A

B-cell lymphoma (MCL and CLL) just like ibrutinib

90
Q

Acalabrutinib also targets what niche thing?

A

Cys481

91
Q

what is rapamycin more commonly known as?

A

Sirolimus

92
Q

what do the rapamycin analogs (sirolimus) inhibit?

A

the fxn of mTOR

93
Q

wtf is mTOR

A

a serine-threonine kinase

94
Q

T or F:
Everolimus inhibits both mTORC1 mTORC2

A

False, it only inhibits mTORC1

95
Q

Everolimus has a second therapeutic use that isnt for oncology reasons, what is it?

A

organ transplants

96
Q

T or F:
Targeted therapies (kinase inhibitors) avoid many toxicities that other products can cause

A

true

97
Q

what kind of DNA is used from lung cancer biopsies to determine drug therapy

A

GENOMIC

98
Q

Oncotype Dx helps to predict ________ and therefore can prevent overtreatment, but these tests (do/do not) drive indications for specific therapies

A

recurrence
do not

PHRM 864 (28 decks)

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