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Eukaryotic Gene Expression > L8 - Therapeutic Strategies that target txn > Flashcards

L8 - Therapeutic Strategies that target txn Flashcards

1
Q

What is a potential therapeutic for MYC but what is the problem?

A

siRNA or shRNA to deplete target

Hampered by problems of delivery and cellular uptake

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2
Q

What are small molecule drugs?

A

Small (400Da) cell permeable molecules

Structure must be well known

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3
Q

What are the targets of small molecule drugs but what is the problem with this?

A

Have small hydrophobic involutions involved in protein interactions
Problem - interactions between TFs often large flat and featureless

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4
Q

What do nutlins do?

A

Occupy p-53 binding pocket of MDM2 and prevent inactivation of p53

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5
Q

How have clinical trials for nutlins gone?

A
  • Increased p53 and p21 confirming it reached its target

- All patients suffered haematological toxicity

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6
Q

What are stapled peptides>

A

Have a hydrocarbon crosslink conferring protease resistance and better stability

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7
Q

What is an example of a stapled peptide and how effective is it?

A

SAH-p53-8 (mimics p53 acitivation domain)

Suppress growth of MDMX driven tumour xenografts in mice

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8
Q

How do stapled peptides get into cells?

A

Too big to diffuse so requires pinocytosis

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9
Q

What is CX-5461

A

Cell permeable small molecule that selectively inhibits rRNA synthesis by pol1

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10
Q

What changes contribute to elevated rRNA txn by pol1 in cancers?

A
  • RB binds UBF and prevents from recruiting SL1 and CBP (lost when RB inactivated)
  • SL1 bound and repressed by p53 (p53 inactivated in cancers)
  • Erk hyperactivated in cancers to phosphorylate and activate TIF-IA
  • Increased MYC increases pol1 stimulation
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11
Q

How does CX-5461 work?

A

Inhibits pol1 txn complex assemply (blocks binding of SL1)

Sensitivity varies wildly between cell lines

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12
Q

How does CX-5461 induce p53?

A
  • inhibits rRNA synth so lots of free ribosomal proteins

- MDM2 can be bound and inhibited by free ribosomal proteins (eg RPL11), releasing p53 from degradation

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13
Q

What happened to lymphoma cells treated with CX-5461?

A

Cells with WT p53 died at much lower doses

Suppressed growth of lymphomas in mice

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14
Q

Why is CV-5461 tolerated in mice when it should kill all cells (lack of rRNA)?

A

Normal mouse tissues make far more rRNA than necessary so that suppression does not trigger stress response or activae p53

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15
Q

What are HATs again? and what are they for?

A

histone acetyltransferases

recruitment is key mechanism of txn activation by p53 and acetylation stabilises p53 by inhibiting binding to MDM2

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16
Q

What do HDACIs do?

A

Inhibit HDACs to raise acetylation levels

17
Q

How do HDACIs work?

A

Occupy HDAC active site blocking substrate with hydrozamic acid group chelating a catalytic Zn2+ - aliphatic linker joins with a capping group

18
Q

Why is it unclear why HDACIs work?

A

Although HDAC inhibition promotes expression of p53 and targets,
MYC also recruits HATs and RB rcruits HDACs so HDACIs would be predicated to enhance MYC function and inhibit RB function

19
Q

What is AML?

A

Acute myleloid leukaemia - disorder characterised by clonal expansion and accum of immature haematopoietic precursors

20
Q

What is RAR?

A

Retinoic acid receptor

21
Q

What is retinoic acid important for?

A

Activate metabolite of vit A
Important for cell differentiaition, embryonic development and adult haematopoiesis
Deficiency causes anemia

22
Q

What is APL and what is characterised by?

A

Acute promyelocytic leukaemia

Chromsomal translocations that fuse RARa gene to PML gene

23
Q

What are the internal symptoms of APL?

A

RXR/PML-RARa heterodimer binds many DNA sites - recruits HDACs and represses txn

24
Q

How is arsenic used to treat APL?

A

Arsenic trioxide binds arsenic to PML/RARa and this attracts SUMO ligase Ubc9 which sumoylates and then ubiquitinated by RNF4 and degraded

25
Q

What is JQ1?

A

Candidate ligand to block bromodomain of BRD4 and block binding to peptides with acetylated lysine (displaces BRD4 from chromatin)

26
Q

What disease is BRD4 involved in and how?

A

NUT midline carcinoma

Chromosomal rearrangements in NUT gene which is fused to BRD4

27
Q

How does JQ1 work?

A

Released BRD4-NUT from chromatin triggering apoptosis of NUT midline cells

28
Q

What is a key target for BRd4 and what does this mean for JQ1?

A

MYC gene

JQ1 can suppress MYC exp

29
Q

How did they test if mice treated with inhibitors relapse?

A

Had mice that had MYC inhibitor with dox activator

Almost all succumbed but 2/12 survived 20 weeks after being given 10 days of dox

30
Q

How can JQ1 by used as a male contraceptive?

A

Brdt is a BET family in testis involved in meiosis and differentiation
JQ1 supresses sperm number and causes sterility with out affecting hormone levels

Eukaryotic Gene Expression (8 decks)

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