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Molecular And Cellular Pharmacology > Kinase Inhibitors > Flashcards

Kinase Inhibitors Flashcards

1
Q

How may Kinases are ther ein the human genome and how many families?

A

500 kinases

About 20 families

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2
Q

Why are kinases difficult to target?

A

Highly conserved catalytic domain amongst families (lack of specificity)
Inhibitors have to compete with high ATP concentration [2mM] so high doses would be needed
Kinases inhibition would produce many ADRs due to lack of specificity

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3
Q

Why is targetting kinases important?

A

Mutant kinases can become oncogenes and drive cancer = clinical need for specifically targeted kinase inhibitors

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4
Q

Name a disease which is has targeted drug therapy and what is this drug target?

A

Chronic Myeloid leukaemia targets the Bcr-Abl fusion protein which has tyrosine kinases activity

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5
Q

What is CML?

A

Myeloproliferative disorder of haemopoetic stem cells

CML blood film will have many granulocytes

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6
Q

What is some epidemiological data on CML?

A

1-2 per 100,000 person years
Median age of onset = 53
15-30% of all leukaemia
Incidence increases with age

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7
Q

Describe the clinical corse of CML

A

Chronic phase
Accelerated phase
Blast crisis

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8
Q

What are some features of the chronic phase?

A

85% of people diagnosed here
Lasts 4-5 years
Normally differentiated granulocytes but excess of them

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9
Q

What are some symptoms which occur is the accelerated phase?

A

Spenomegaly
Leukocytosis
Fever (infections)
Throbocytopenia or cytosis

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10
Q

How long does the accelerated phase occur for?

A

6-9 months

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11
Q

What are some blood characteristics on the accelerated phase?

A

15-29% blasts in blood

>20% basophils

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12
Q

What is the mean survival rate for the blast crisis?

A

3-6 months

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13
Q

What has happened to the granulocytes in blast phase?

A

They are non functioning poorly differentiated) with many molecular abnormalities within their DNA

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14
Q

What are the blood characteristics of the blast phase?

A

(Greater than or equal to) 30% blasts in blood

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15
Q

Symptoms of blast phase?

A

Fever, night sweats, bone pain, weight loss

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16
Q

What is the characteristic molecular abnormality in CML

A

Presence of Philadelphia chromosome (95% of cases)

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17
Q

What is the Philadelphia chromosome?

A

Reciprocal translocation between chromosome 9 and 22

T(9;22)(q34;11)

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18
Q

What genes are located on chromosome 9 and 22 which are important for CML?

A

9 = Abl

22=Bcr

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19
Q

What does translocation of part of 9 to 22 do?

A

Causes the juxtaposition of abl and Bcr on chromosome 22

Forms fusion protein Bcr-Abl when transcription and translation occurs

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20
Q

How is Bcr-Abl and oncogene?

A

It has constitutive tyrosine kinase activity which activate cell cycle proteins and enzymes which
Increase cell division,
Inhibits DNA repair
And promotes genetic instability which causes mote mutations in DNA (blast crisis)

21
Q

What is the normal function of Abl?

A

A kinase with similar properties to Src kinase

22
Q

What prevents physiological Abl activation?

A

There is autoinhibtion of the kinase activity by the SH2 +SH3 domain clamp
And the N terminal which is Myristoylated acts as a latch
Both prevent activation

23
Q

What causes the normal Abl to unclamp?

A

Exposure to proline rich sequences or phosphorylated tyrosine
These bind to the SH3 and SH2 domains respectively

24
Q

When able is unclamped what is allowed to occur?

A

Releases abl from autoinhibition which allows activation of the 2 kinase domains
These auto phosphorylate tyrosine 245 and tyrosine 412 (on activation loop)
This increases tyrosine kinase activity of the fusion protein which drives cancer

25
Q

How does Brc disrupt normal Abl function?

A

Bcl will be fused onto he N terminus which means N terminal doe snot act as a latch to prevent activation.
This means that Abl will be active without the need for proline rich or phosphorylated tyrosine interaction and will be constitutively active

26
Q

What is the implication of constitutively active Bcr-Abl?

A

You get defective cell adhesion and growth factor independence as RTKs do not need to be activated for protein to function
You get expansive growth and resistance of apoptosis

27
Q

When will imatinib bind to Bcr-Abl?

A

When tyrosine 412 is not phosphorylated

28
Q

What were the old therapeutic options for treating CML?

A

Allogenic stem cell transplant ion
Interferon alpha
Chemotherapy

(<20% cured)

29
Q

What is the new treatment for CML?

A

Imatinib (Gleevec) which inhibits Bcr-Abl

30
Q

What is the benefit of CML over chemo?

A

Chemo is no selective and targets all rapidly devising cells which included physiological haemopoetic stem cells. Thus normal stem cells not harbouring mutation will be destroyed. Imatinib only targets cells contains the bCr-Abl protein therefore benign cell survive and patient can have a fun ting immune system

31
Q

What is the mechanism of imatinib?

A

Binds to the hydroxyl group on Threonine 315 via a hydrogen bind which blocks the ATP binding site
T315 regulates ATP site access this binding to imatinib inhibits ATP binding and kinase activity

32
Q

What are the effectiveness stats of imatinib?

A

Complete cytogenetic response = 69% at 12 months
87% at 60 months

Only 7% progress to accelerated phase or blast crisis over 5 years

33
Q

What are some side effects of imatinib?

A 
Mainly mild to moderate ones
Headache
Dizziness
Mouth ulcers
Anaemia
34
Q

Why is imatinib most effect in chronic phase?

A

Typically only Bcr-Able mutation in chronic phase
As disease progresses more mutations occur which imatinib does not selectively target.
These mutations are involve din other pathways which drive cancer

35
Q

What are some disadvantages of imatinib?

A

Does not eliminate Bcr-Abl cell so life long therapy needed (expensive)
Less effective in blast crisis and Philadelphia + B cell acute lymphoblastic leukaemia
Resistant CML does exist

36
Q

Name another cancer which has a Philadelphia chromosome?

A

Acute B cell lymphoblastic leukaemia

37
Q

What causes CML resistance?

A

Additional mutations other than bcr-abl (>80% blast phase CML have mutations other than Philadelphia chromosome)
Point mutation in Bcr-abl fusion protein T315I (gate keeper mutation) which means imatinib does not bind
Role of other enzymes

38
Q

Why does the isoleucine point causes resistance?

A

It a bigger amino acid and interacts with residues in the protein which would normally interact with imatinib. Thus imatinib can no longer bind but ATP still can get in

39
Q

How can imatinib resistance T315I be targeted?

A

Less specific kinase blockers whic act on multiplekinases e.g. Pronatinib
Other kinases effected include Src

40
Q

Advantage of pronatinib?

A

Non steric clash with I315 and blocks ATP binding site
Has relative efficacy
cytogenic response in all patients = 54%
Cytogenetic responce in those with T315I mutation = 70%

41
Q

Disadvantages of pronatinib?

A

Less specificity = more ADRs

Abdo pain, N+V, infections, fever, myalgia

42
Q

What is another common mutation in the later stages (blast phase) of CML?

A

P53 mutations
This is a tumour suppressor gene which is stabilised by DNA damage and promotes cell division arrest and apoptosis if defective DNA is detected

43
Q

What does loss of p53 cause?

A

Blast crisis and cell is resistant to apoptosis

44
Q

What are some other potential targets for imatinib?

A

Gastrointestinal stromal tumours caused by c-Kit mutation (RTK for stem cell factor) which arise from the intestinal cells of cajal
Glioblastomas which have PDGF-R mutation
Other leukaemias with constitutively active fusion proteins (Tel-PDGF-R)

45
Q

Which is the responce rate for imatinib for GISTs?

A

60% in phase 1 clinical trials

46
Q

What are future potential therapies?

A

RNAi
GPCR antibodies
Gene therapy

47
Q

How does RNAi work?

A

Give small interfereing RNA (siRNA) or microRNA (double stranded). This binds to dicer which breaks them down into small 21 base long sections.
These then bind to argonaut which selects a single strand (guide strand). Complex formed = RNA induced silencing complex. The RISC binds specifically to mRNA of interest via base pair complementation and causes cleavage of mRNA which is degraded by ribonucleases

48
Q

How can RNAi be used to treat CML?

A

SiRNA complementary for mRNA which forms Bcr=Abl

49
Q

How might GPCR antibodies be useful?

A

Antibody to CCR5 GPCR

Prevent internalisation of HIV

Molecular And Cellular Pharmacology (12 decks)

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