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Pharmacology > Kinases > Flashcards

Kinases Flashcards

1
Q

How many families of kinases in the human genome?

A

~20 families

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2
Q

Why were kinase inhibitors initially thought not to be good targets? (3 reasons)

A

1) inhibitors generally compete with ATP - high intracellular ATP
2) structurally similar active sites
3) importance of kinases in cell function

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3
Q

Kinases play a key role in disease. Which in particular?

A

Cancer

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4
Q

How many kinases inhibitors are in clinical trials?

A

> 30

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5
Q

Why has development of kinase inhibitor drugs increased?

A

Success of GLEEVEC (treating chronic myeloid leukaemia)

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6
Q

What is CML?

A

Chronic myeloid leukaemia

Proliferation disorder of hematopoietic stem cells with a well-characterised clinical course.

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7
Q

CML has a well-characterised clinical course. What are the main phases?

A

Chronic phase

Advanced phases

  • accelerated phase
  • blast crisis
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8
Q

In the chronic phase of CML, what is the nature of the myeloid cells?

A

They are in excess but differentiating normally

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9
Q

In the advanced phases of CML (accelerated phase and blast crisis), what is the nature of the myeloid cells?

A

Accumulated molecular abnormalities. Loss of capacity for terminal differentiation.

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10
Q

What is CML characterised by?

A

The presence of the Philadelphia (Ph) chromosome.

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11
Q

What is the Philadelphia chromosome?

A

The result of a reciprocal translocation between chromosome 9 and chromosome 22, giving rise to a fusion gene, bcr-abl.

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12
Q

Which chromosomes are reciprocally translocation in the Philadelphia chromosome?

A

Chromosomes 9 and 22

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13
Q

Which genes are fused in the translocation that takes place between chromosomes 9 and 22 in the Philadelphia chromosome?

A

C-abl oncogene on chromosome 9(region q34) and parts of bcr (breakpoint cluster region) on chromosome 22(region q11)

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14
Q

What is the technical form for the reciprocal translocation between chromosomes 9 and 22 in the Philadelphia chromosome?

A

T(q;22)(q34;q11)

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15
Q

What is the fusion protein produced by the Philadelphia chromosome?

A

BCR-ABL

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16
Q

Why might BCR-ABL sometimes be referred to as p210?

A

It is 210kDa

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17
Q

What are three clinically important variants of BCR-ABL (p210)?

A

p190
p210
p230

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18
Q

What percentage of patients with CML have the BCR-ABL protein (p210)? What does it cause?

A

95%

Causes a malignant clone

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19
Q

In which 2 main ways does BCR-ABL affect the cell?

A

It is constitutive the active. It activates cell cycle proteins and enzymes, speeding up cell cycle division.
It inhibits DNA repair, causing genomic instability and possibly leading to blast crisis.

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20
Q

How does BCR-ABL affect the cell cycle?

A

It activated cell cycle proteins and enzymes, speeding up the cell cycle and cell division.

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21
Q

How does BCR-ABL affect DNA repair?

A

It inhibits it, causing genomic instability and possibly leading to blast crisis

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22
Q

Which isoform of BCR-ABL (p210 in CML) is associated with acute lymphoblastic leukaemia (ALL)?

A

p190

23
Q

What is a possible splice variant of BCR-ABL (p210), and what disease is it primarily associated with?

A

p190 - ALL (acute lymphoblastic leukaemia)

24
Q

What does the Abl gene encode?

A

An oncogene. - a membrane associated protein (tyrosine kinase)

25
Q

What type of protein does the oncogene Abl encode?

A

Membrane-associated tyrosine kinase

26
Q

Which part of the BCR-ABL protein is responsible for the tyrosine kinase activity?

A

ABL

27
Q

What are the functional consequences of constitutively active BCR-ABL?

A

1) Defective cell adhesion
2) Growth factor independence

Which leads to

1) expansion
2) growth advantage
3) resistance to apoptosis

28
Q

Give three non-selective therapeutic treatment options for CML

A

1) Allogenic stem transplantation (Ph+ cells derived from haematopoietic stem cell)
2) Interferon-alpha (IFN-alpha)
3) Chemotherapy

29
Q

How can CML be selectively targeted?

A

Inhibition of BCR-ABL

-GLEEVEC

30
Q

What does Gleevec do?

A

Inhibits BCR-ABL to treat CML

31
Q

What is the mechanism of action of Gleevec?

A

HYDROXYL group forms a hydrogen bond with T315 of BCR-ABL.

Side chain controls binding to hydrophobic regions next to ATP-binding site

Termed the ‘gatekeeper’ residue

GLEEVEC binds to a INACTIVE conformation and blocks ATP binding

32
Q

Which conformation of BCR-ABL does gleevec bind to? What is the effect of this?

A

INACTIVE confirmation and blocks ATP binding

33
Q

What is Gleevec used for?

A

Inhibiting the molecular cause of CML (BCR-ABL)

34
Q

How many kinases in the human genome?

A

500

35
Q

What is the safety profile of Gleevec?

A

Adverse effects mild to moderate - only 5% had to discontinue.
Long-term treatment required.

36
Q

When is Gleevec particularly effective? In which phase of CML?

A

In interferon-alpha-resistant chronic phase (some efficacy in other phases but OTHER MUTATIONS may drive blast phase)

37
Q

Why may Gleevec not be effective in the treatment of advanced phase Blast Phase CML?

A

Because other mutations (not just BCR-ABL) may drive the blast phase

38
Q

Some patients are resistant to Gleevec. Why might this be?

A

Gleevec-resistant BCR-ABL mutants - block binding or block generation of inactive form.

Ie gatekeeper mutation of threonine315 (eg mutated to isoleucine - T315I)

39
Q

What is the gatekeeper residue in BCR-ABL, that forms a hydrogen bond with the Gleevec hydroxyl?

A

Threonine315

40
Q

What is the gatekeeper residue frequently mutated to in BCR-ABL in patients resistant to Gleevec?

A

Threonine to isoleucine

…T315I

41
Q

How can Gleevec-resistant mutants be targeted?

A

1) T315I mutant inhibitors
2) Target Auroroa kinase
3) Probatinib (multikinase -Src, BCR-ABL- inhibitor)

42
Q

Aside from T315I mutations in BCR-ABL, why may patients be resistant to Gleevec?

A

Other enzymes (associated with BCR-ABL but independent of activity)

> 80% blast phase CML have genetic aberrations in addition to Ph chromosome

43
Q

Why is p53 normally at low levels in the cell?

A

Short half life due to ubiquitination and proteolysis

44
Q

How is p53 stabilised?

A

By DNA damage

45
Q

How can loss of p53/ mutations in p53 affect CML?

A

Result in blast crisis
Cell cycle arrest
Apoptosis
Differentiation

46
Q

Aside from BCR-ABL, what are other molecular targets of Gleevec?

A

PDGF-R

c-Kit

47
Q

What is PDGF-R?

A

Platelet-derived growth factor receptor

48
Q

How is PDGF-R implicated in:

  • leukaemias
  • glioblastoma
A

1) constitutively active fusion protein (Tel-PDGF-R)

2) autocrine loop involving PDGF in glioblastoma (currently incurable)

49
Q

What is c-Kit?

A

An RTK for stem cell factor

50
Q

Activating mutations of the RTK c-Kit are associated with the number of tumour types. Give an example.

A

GI stromal tumours

51
Q

How might siRNA have a use in CML?

A

By silencing bcr-abl mRNA

52
Q

Give an example of a therapeutic antibody against TNF-alpha. What is it used to treat?

A

Anti-tumour necrosis factor alpha (anti-TNFa)

Used to treat rheumatoid arthritis, Crohn’s, plaque psoriasis

53
Q

There are several mechanisms through which kinase inhibitors can exert their actions. Give some.

A
  1. Most prevalent = blocking readily ‘druggable’ ATP binding site where phosphate transferred to substrate
  2. Activating phosphatase to accelerate removal of substrate - not yet exploited

Pharmacology (13 decks)

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