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PHRM 864: Therapeutics IV > Kinase Inhibitors [NEED TO FINISH] > Flashcards

Kinase Inhibitors [NEED TO FINISH] Flashcards

1
Q

What is one key structure that all the kinase inhibitors have in common?

A
  • Have away to mimic ATP binding
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2
Q

In what way is cell singaling largely driven by?

A
  • The ransfer of phosphates via ATP
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3
Q

What is the most common target of Kinase activity?

A
  • Tyrosine
  • Also Serine and Threonine
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4
Q

What way is there balancing of kinase activity?

A
  • Phosphatases remove phosphates = oppse the action of the kinases
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5
Q

What are the types of Kinase Inhibitors?

A
  • Type I: Bind to the active kinase
  • Type II: Bind & stabilize the inactive kinase
  • Type III: allosteric binding
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6
Q

What amino acids is not a target of phosphorylation?

A
  • Alanine
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7
Q

What is the source of the phosphate that gets transferred onto a substrate by a kinase?

A
  • ATP
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8
Q

What are the EGFR kinase inhibitors?

A
  • Gefitinib, Afatinib, Osimertinib
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9
Q

What is Gefitinib?

A
  • Type I TKI
  • Re approved for NSCLC in 2015
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10
Q

What is Gefitinb used for?

A
  • Treatment of EGFR mutant metastatic NSCLC
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11
Q

What is the mechanism of action for Afatinib?

A
  • Covalent inhibitor for ALL EGF receptors
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12
Q

What is Afatinib used for?

A
  • Treatment of EGFR mutant metastatic NSCLC
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13
Q

What are some tests that you should take to see if Afatinib could be useful?

A
  • Exon 19 deletion
  • Exon 21 substitution
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14
Q

For the EGFR kinase inhibitors, is a rash a good thing to have?

A
  • YES; it should that the drugs is actually working within the body
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15
Q

In what way is there resistance toward Gefitinib and Afatinib?

A
  • T790M
  • Exon 19 deletion & Exon 20 substitution GOOD
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16
Q

What EGFR kinase inhibitor could you use to get around the T790M resistance?

A
  • Osimertinib - comformation is different
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17
Q

What is Osimertinib?

A
  • 3rd Gen EGFR inhibitor
  • Covalent inhibitor
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18
Q

What is Osimertinib used for?

A
  • Treatment of EGFR mutant metastatic NSCLC that HAS the T790M resistance mutation [1st line]
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19
Q

What is HER2 mostly found in?>

A
  • Breast Cancer
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20
Q

What are the drugs that affect HER2?

A
  • Lapatinib & Tucatinib
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21
Q

What is the mechanism of action for Lapainib?

A
  • Binds to BOTH HER2 and EGFR inhibiting them but is selective for HER2
22
Q

What is Lapatinib used for?

A
  • HER2 Selective breast cancer
  • Treatment of metastatic breast cancer with Capecitabine
23
Q

What are some of the side effects for Lapatinib?

A
  • Diarrhea, Nausea, Vomiting [blocking BOTH]
  • Decreased Cardiac function [HER2}
24
Q

What are Dacomitinb, Neratinib & Afatinib approved for?

A
  • Dacomitinib & Neratinib = Breast and Lung
  • Afatinib = NSCLC
25
Q

What is the mechanism of action for Tucatinib?

A
  • Binds ONLY to HER2 and blocks it - HER2 selective
26
Q

What is the way that Tucatinib is used?

A
  • 2nd line treatment for metastatic breast cancer with Trastuzumab & Capecitabine
27
Q

What are some of the side effcets for Tucatinib?

A
  • Less the Lapatinib BUT still cardio issues
28
Q

What is FMS-like Tyrosine Kinase 3?

A
  • Ligand that helps with Hematopoietic Cell Growth
  • Mutation cause growth but NO death
29
Q

What is the way that FLT3 gets mutated

A
  • Internal Duplication [ITD] of the kinase receptor in juxtamembrane domain
30
Q

What disease does FLT3 affect?

A
  • AML: Acute Myeloid Leukemia
31
Q

What are the FLT3 Inhibitors?

A
  • Midostaurin [1st gen = TOO broad]
  • Crenolanib [2nd gen = more specific]
  • Quizartinib [3rd gen = FOR ITD mutation]
32
Q

What is an example of Transolation of genes?

A
  • Bcr-Abl
33
Q

What is the special Chromosomal Translocation called?

A
  • Philadelphia Chromosome [Ph1]: when 5’ Bcr is joined to 3’ Abl
  • Found in 95% of chronic myeloid leukemia
34
Q

What is the mechanism of action for Imatinib?

A
  • [Type II]Inhibition of Abl that results in a decrease of proliferation and increase cell death in CML and GIST
35
Q

What are some toxicities for Imatinib?

A
  • Nausea & Vomiting
  • Edema
  • Neutropenia & Thrombocytopenia
36
Q

What is important to know about Imatinib?

A
  • LIFE LONG treatment
37
Q

What is the mechanism of action for Ponatinib?

A
  • The Bcr-Abl inhibitor
38
Q

What is important to know about Ponatinib?

A
  • Can inhibit the “gatekeeper” mutation T315I [which blocks Imatinib]
39
Q

What is BRAF?

A
  • Helps make RAF that increases cell growth
  • BRAF v600 is the mutation
40
Q

What is the mechanism of action for Dabrafenib?

A
  • BRAF v600 inhibitor that blocks BRAF v600 but activates normal BRAF
41
Q

What is the used of Dabrafenib?

A
  • Treatment of Melanoma with BRAF v600
  • Good for NSCLC with BRAF v600
  • NOT for colorectal cancer with BRAF v600
42
Q

What is the mechanism of Trametinib?

A
  • Inhibits the kinase activity of MEK1 and MEK2
43
Q

What is important to know about Trametinib?

A
  • Used in combo with Dabrafenib?
  • Type III inhibitor
44
Q

What are the side effects for Trametinib?

A
  • Rash
  • Diarrhea
  • Lymphedema
45
Q

What is the importance of Bruton Tyrosine Kinase [BTK] in B cells?

A
  • Helps with Normal B Cell activity and B Cell tumor growth
46
Q

What are the BTK inhibitors?

A
  • Ibrutinib & Acalabrutinib
47
Q

What is important to know about Acalabrutinib?

A
  • 2nd Gen Covalent BTK inhibitor
  • Treatment for B cell lymphoma
  • Stronger than Ibrutinib
48
Q

What are the rapalogs?

A
  • “limus”
  • Inhibit the function of mTOR [Serine-Theronine Kinase]
  • Can inhibit the immune response by blocking IL-2
49
Q

What is unique feature of the rapalogs?

A
  • Big ring structure
50
Q

What is the major problem with Kinase inhibitors?

A
  • Resistance: most of the time the dugs will work but can develop resistance causing symptoms to come back

PHRM 864: Therapeutics IV (28 decks)

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