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Pharm Decks > Lecture 12 - New targets in Chemo > Flashcards

Lecture 12 - New targets in Chemo Flashcards

1
Q

Fundamental principles of the outcomes of DNA damaging therapies

A
  • If you can recover the damage by a repair mechanism from the drug then you have failed
  • If you can inhibit the repair mechanisms you can get a better result
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2
Q

Example of a drug & target where there is direct inhibition of a repair enzyme

A

Enzyme targeted: MGMT

Drug: O6-Benzylguanine, patrin

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3
Q

Examples of targets of inhibitors of DNA control systems

A
  • PARP-1
  • Checkpoint kinase
  • DNA dependent protein kinases
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4
Q

Example of PARP-1 inhibitors

A
  • Olaparib
  • rucaparib
  • veliparib
  • niraparib
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5
Q

Where do alkylating agents preferentially alkylate in DNA?

A

N7 position

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6
Q

What is another site which DNA alkylators target in DNA, other than the most common one?

A

O6-alkyl guanine

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7
Q

What removes O6-alkyl guanine in DNA?

A

MGMT enzyme

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8
Q

How can resistance to O6-alkylators be overcome and drugs for this?

A
  • By MGMT depletion
  • Thus making the DNA more susceptible to damage from the O6 lesions
  • O6-Benzylguanine and Partin in clinical trials
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8
Q

What is the issue with depleting MGMT?

A
  • Can cause myelosuppression
  • lower doses of alkylating agents would be required
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9
Q

What is PAR?

A

The third nucleic acid in mammalian cell
- Poly(ADP-ribose)

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10
Q

Features of PAR

A
  • Polyanionic polymer
  • linear or branched
  • built from ADP-ribose units derived from NAD+
  • Usually build onto Glu side chains in target proteins
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11
Q

What substrate do PARPs use?

A

NAD+

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12
Q

What is PARP-1?

A
  • Poly(ADP-ribose)polymerase-1
  • Found in nuclei
  • essential for initiating DNA repair
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13
Q

What is the reaction of PARP-1?

A
  • PARP-1 uses NAD+
  • Forms intermediate, then lone pair of electron on Oxygen forms a double bond
  • Break the carbon bond
  • Oxygen quenched by reaction with an alcohol
  • Forms polymer chain
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14
Q

What is the structure of PARP-1?

A

N terminal –> C terminal

  • DNA binding domain with 2 ZNF
  • Auto modification domain containing GLUTAMATE with Nucleuar localisation signal and caspase-3 cleavage site
  • NAD+ binding domain
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15
Q

Where does polymerisation occur in PARP-1?

A

at NAD+ binding domain

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16
Q

What role does PARP-1 play?

A

Repairing damaged DNA

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17
Q

Steps in repair of DNA by PARP-1

A
  1. SSB
  2. PARP-1 recruited to damage, forms PAR chain on histone near damage
  3. Histone removed from DNA
  4. Repair enzymes bought to damage
  5. PARP-1 adds PAR chains to itself, removal of PARP-1
  6. PARG snips PAR chains off PARP-1 and histone
  7. return back to repaired DNA with histone and PARP-1 back in place
  • Inhibition of PARP-1 = no base repair
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18
Q

What is the cancer therapeutic application of inhibition of PARP-1?

A
  • Radiotherapy, cytotoxic electrophilic drugs and inhibitors of topisomerase II cause DNA SSB
  • If you can repair via PARP-1 then cells survive
  • Inhibit PARP-1 to inhibit repair and potentiate these therapies
19
Q

What is the other therapeutic applications of inhibition of PARP-1?

A
  • Reduction of organ damage following reperfusion injury
20
Q

Regarding drug design of inhibitors of PARP, what important obstacle was discovered which prompted new drug design of PARP-1 inhibitors

A

Full analogues of NAD+ such as TAD do not inhibit PARP activity as they are inacitve

21
Q

When designing a drug to inhibit PARP-1, what features of simple analogues DONT make a difference when wanting to increase potency of the inhibitor?

A
  • Polarity of 3-subsituent
  • Hydrogen bonding
  • Size
22
Q

When designing a drug to inhibit PARP-1, what features of simple analogues are favoured to increase potency of the inhibitor?

A
  • electron neutral or electron donating group in the ring (pushes the electron density towards)
  • Side chain on 3rd position of ring (not 2nd or 4th)
  • Amide group > sulphur group as side chain
  • Control of steric clashes/conformation by building another ring/benzene ring to lock amide in place
  • A bulkier subsitent
23
Q

When designing a drug to inhibit PARP-1, what features of simple analogues are disfavoured to increase potency of the inhibitor?

A
  • Electron withdrawing groups which pull electron denisity away from the ring (DONT WANT A NITROGEN)
  • Side chain on 2,4 position of ring
  • Steric clashes
24
Q

Examples of PARP-1 inhibitors

A
  • Olaparib
  • Rucaparib
  • Veliparib
  • Niraparib
25
Q

Features of Olaparib

A
  • Inhibits PARP 1,2,3
  • Ovarian, fallopian tube and primary peritoneal cancer
26
Q

Features of Rucaparib

A
  • Inhibits PARP-1, PARP-2, tankyrase-1, tankyrase-2
  • For ovarian, fallopian tube, peritoneal cancer AND treatment of patients with BRCA mutation (germline and/or somatic) taking platinum-based chemotherapy
  • in combination with temozolomide
27
Q

Features of Veliparib

A
  • Inhibits PARP-1, PARP-2, tankyrases
  • Discontinued in trials
28
Q

Features of Niraparib

A
  • Inhibits PARP-1, PARP-2, PARP-4, tankyrases
  • ovarian, fallopian and peritoneal cancer after response to first line platinum therapy
29
Q

Overview of achieving synthetic lethality (BRCA-1/2)

A
  • cancer cells have damage repair mechanism
  • Damaged base gives a SSB, this can be repaired by BER with PARP-1 playing a role and the cell would survive
  • DSB leads to HR and cell survives
  • A persistent break would lead to cell death
  • Patients can be heterozygous for mutant BRCA1/2, but the tumour could be homozygous
  • means tumour might be unable to perform HR on DSB and if you inhibit PARP-1 then you might end up with synthetic lethality, you kill the cells
  • PARP-1 as a single agent
30
Q

What are the typical features of a tumour?

A
  • Poor vascular structure
  • Disorganised network
  • leakiness
  • high internal pressure
31
Q

What regions are present in tumours?

A

Oxic region
Hypoxic region
Necrotic region
Function blood vessel

32
Q

Sensitivity to chemo and radiotherapy of the Hypoxic and Oxic region of tumours

A

Oxic - sensitive
Hypoxic - insensitive

33
Q

How can hypoxia be a therapeutic opportunity?

A
  • Radiotherapy requires O2 –> hypoxic tissue less sensitive to radiotherapy
  • radiosensitsing drugs & PARP-1 inhibitors –> increase sensitivity
  • Can use hypoxia selective drugs –> behave as prodrugs in oxic tissue –> only display toxicity in hypoxic regions
34
Q

Example of a radiosensitising drug

A

Etanidazole

35
Q

How do Oxygen-mimetic radiosensitizers work?

A
  • work in hypoxic cells
  • replace oxygen in the chemical reactions that lead to DNA damage
36
Q

How does Etanidazole work?

A
  • radio sensitising drug
  • Reduces glutathione concentration
  • inhibits glutathione S-transferase
  • tissues become more sensitive to ionising radiation
37
Q

How do hypoxia selective drugs (prodrugs) work?

A
  • target the hypoxic cells of tumours –> which cause resistance to conventional therapies
  • inactive in normal tissues that are well oxygenated, but becomes active at the low oxygen levels
38
Q

Examples of Hypoxia selective prodrugs

A
  • Mitomycin C
  • Nitromidazole
39
Q

In a hypoxia associated tumour microenvironment, what is the correlation of resistance and oxygen levels?

A
  • Drug resistance increases in a tumour as the oxygen level decreases
40
Q

Therapeutic approaches targeting telomerase/telomeres

A
  • Inhibition of telomerase activity –-> binding to G-quadruplex
  • Inhibition of tankyrase-1 –-> preventing telomerase from binding to telomere
41
Q

Why is MGMT not considered a proper enzyme?

A
  • not regenerated
  • 1:1 stoichiometric
42
Q

What is the rationale for combination therapy of Temozolomide with pseudo substrates for MGMT?

A
  • TMZ resistance mediated by MGMT protein
  • Tumours lacking MGMT activity –> more sensitive to TMZ
43
Q

Why would we want to target PARP-1 with inhibitors in the context of Reduction of organ damage following ischaemia/reperfusion injury?

A
  • Blood supply to an organ interrupted –> cells hypoxic
  • Reperfusion –> rapid resupply of O2 to the hypoxic cells
  • O2 –> oxidising diradical –> damages DNA
  • PARP-1 over-activated
  • Cells depleted of NAD+
  • Cells die and organ failure
44
Q

Methods to overcome hypoxia

A
  • reduce cellular oxygen consumption
  • Increase tumour oxygenation

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