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Cancer > Drug Discovery > Flashcards

Drug Discovery Flashcards

1
Q

What do cancer drugs do?

A

Ideally target cancer cells without targeting normal cells.

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2
Q

What factor might stop a candidate therapy from working as it was intended?

A

If it targets a vital function of normal cells.

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3
Q

What safety precautions need to be taken when first testing a drug in humans?

A

Very small groups

Very low dose.

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4
Q

What needs to be done before a candidate therapy can be tested in humans?

A

Test in animals e.g. rats, monkeys

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5
Q

What outcomes would be used to determine if a therapy works?

A

Tumour stops growing or shrinks.
Increased life expectancy.
No metastases.

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6
Q

What can be a problem when testing a new drug?

A

Cancers are usually treated by multiple drugs, it’s difficult to test/see the effect of an individual drug.

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7
Q

What are the current cancer treatment options?

A 
Surgery 
Radiotherapy
Chemotherapy
Endocrine therapies (tamoxifen)
Biotherapies (antibodies, vaccines)
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8
Q

Why do we need new cancer therapies?

A

Cancer survival rates are improving, mainly due to improved therapies, BUT, incidence is rising.

For many cancers, current therapies are ineffective.

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9
Q

What are the advantages of chemotherapy?

A

Chemotherapy is the main systemic treatment option in cancer therapy.

Metastasis is the major cause of mortality in cancer. Only systemic treatment could target metastasis.
Some primary tumours may be inoperable.
Some tumours respond very well to chemotherapy.

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10
Q

What was the first cyctotoxic chemotherapeutic?

A

Nitrogen Mustard

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11
Q

How did people originally search for anti-cancer agents?

A

Drug developers aimed to find as many agents as possible capable of inhibiting tumour growth using in vivo mouse tumour models.

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12
Q

What are the disadvantages of cytotoxic agents?

A

Targets usually not known in advance. DNA is the common target of all classes of cytotoxic agent. By interfering with DNA, most conventional agents mainly target dividing cells:

Narrow therapeutic window.
Not all tumours respond.
Multi-drug resistance is a big problem.

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13
Q

What are the major classes of cytotoxic agents?

A 
Alkylating agents
Platinum agents
Plant alkaloids
Anit-tumour antibiotics
Anti-metabolites
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14
Q

Which cyclins/CDKs mediate each of the cell cycle check points?

A

M - (spindle checkpoint) Cyclin B/CDK1

G0/G1 - Cyclin D/CDK4&6

G1/S - Cyclin E/CDK2

S - Cyclin A/CDK2

G2/M - Cyclin A/CDK2

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15
Q

What is the DNA damage pathway?

A

DNA damage - ATM/ATR - p53 - p21 - inhibits cyclin/CDK (this stops cell cycle progression)

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16
Q

What are the phases of drug development?

A
  1. Target identification
  2. Assay development
  3. Compound screening
  4. Hits to leads
  5. Lead optimisation
  6. Preclinical efficacy
  7. ADMET
  8. Phase 1
  9. Phase 2
  10. Phase 3
  11. Approval phase
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17
Q

What is the developmental cost of a new agent?

A

About $800M

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18
Q

What are the ideal drug target characteristics?

A
  1. Specific expression in target tissue.
  2. Causative role in disease aetiology.
  3. Should be druggable.
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19
Q

What percentage of CML patients have the Philadelphia chromosome?

A

95%

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20
Q

Which genes are fused in the Philadelphia chromosome?

A

Bcr-Abl

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21
Q

Which drug is a targeted cancer therapy used for CML?

A

Imatinib (Gleevec)

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22
Q

How does Gleevec work?

A

It blocks ATP binding to Bcr-Abl, preventing substrate phosphorylation.

It does this by binding both the active site and active loop in c-Abl, this stabilises a closed loop conformation.

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23
Q

Which type of cancer is HER2 frequently over-expressed in?

A

Breast cancer

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24
Q

What is herceptin?

A

Monoclonal antibody against HER2, it blocks receptor and causes Ab-dependent toxicity.

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25
Q

Which enzyme is expressed in most cancer cells and is essential for limitless replication?

A

Telomerase

26
Q

Name two telomerase subunits.

A

hTERT - telomerase reverse transcriptase

hTR: telomerase RNA

27
Q

Which drug is being developed to target telomerase?

A

Imetelstat

28
Q

How does imetelstat work?

A

An oligonucleotide inhibitor. It is complimentary to the hTR template. It base pairs to the hTR, blocking hTERT access.
Inhibits telomerase activity in cancer cells.
Telomeres shorten killing cancer cells but not normal cells (no telomerase)

29
Q

How do compound libraries work?

A

They are compound collections probed for hits in screening assays.

Industrial screening libraries may contain 1-2M compounds.

30
Q

What are the classes of compound libraries?

A

Diversity: high chemical diversity - few similar compounds.
Focused: features of known ligands for target calss
Fragment: low molecular weight (100-300)
Natural products: highly complex molecules- often R05 non-compliant

31
Q

How do screening assays work?

A

Report some aspect of target activity in multi-well format.
Compounds added to plate (1 per well)
Compounds resulting in a change in assay readout - “hits”.
Hits are re-tested in secondary assays to confirm activity/specificity.
Chemical optimisation for maximal activity generates “leads”

32
Q

What should be considered when developing an assay?

A 
Detection of relevant target activity (enzyme activity, ligand binding, transcription, dimerisation etc.)
Technology platform 
 - cell based or biochemical
 - luminescence, fluorescence, colourimetric or radioactivity?
 - manual or automated
 - plates and readers
Assay throughput
 - low throughput, high throughput?
33
Q

Which factors determine which assay is used?

A 
How the target is measured.
What the biological context is.
How expensive the reagents are.
How big the library is.
etc.
34
Q

What are the advantages of cell based assays?

A

Possible to screen multiple pathways affecting target.
Target is in native conformation.
Cell impermeable/toxic compounds excluded early.

35
Q

What are the disadvantages of cell based assays?

A

Extensive target deconvolution may be necessary.

Possible indirect effects on assay readout.

36
Q

What the advantages of biochemical assays?

A

Target of compound is known and purified.
Easy to study structure/activity relationships & IC50
Rapid progression to structural studies.

37
Q

What are the disadvantages of biochemical assays?

A

Requires sufficient purified target for the screen.

Target is in a single conformation.

38
Q

How can promoter activity be measured using luminescence?

A

By controlling luciferase expression with a gene promoter.

More light = more luciferase = more promoter activity.

39
Q

Give an example of luciferase being used in drug development.

A

Telomerase is overexpressed in cancer cells. Using luciferase controlled by a telomerase gene promoter, compounds were identified which turn down telomerase expression.

40
Q

What are the advantages and disadvantages of fluorescence assays?

A

Advantages: Many colours available for multiplexing; high brightness

Disadvantages: high background, possible compound fluorescence.

41
Q

Give an example of a use of a fluorescence assay.

A

p53 localisation.
Nuclear p53 transcriptionally regulates checkpoint and apoptosis genes. An imaging assay was designed to identify compounds which promote p53 nuclear localisation.
Genetic fusion of GFP to the DNA coding sequence of a protein of interest allows us to track where in the cell the protein is expressed by fluorescent imaging. Every molecule of expressed protein will fluoresce because of GFP.

42
Q

How do fluorescence assays for purified enzymes work?

A

They are designed by incorporating a label in the enzyme substrate. Enzyme activity should activate or block the label.

43
Q

How do secondary assays identify and optimise the best hits?

A 
Confirm activity (rule out false hits)
Confirm specificity against target
Confirm molecular effects
Confirm biological effects
Selecting most active compounds.
44
Q

What is the main aim of the secondary assay?

A

Determining which cellular pathways are affected by the drug. So that you can know the effects are consistent with target inhibition.

45
Q

What is meant by lead optimisation?

A

Improve compound activity/specificity/binding affinity.
Compound series generated by modifying peripheral groups on hit scaffold.
Test new analogues in assays to determine structure/activity relationship
Best candidates usually have low nM activity.

46
Q

Which kind of assays would be used in vitro to test pre-clinical efficacy?

A

Cell proliferation assays
Cell viability assays
Apoptosis and senescence assays.

47
Q

What is the conventional approach to in vivo models of pre-clinical efficacy?

A 
Implant cells in immune deficient mice.
Wait for tumour formation.
Measure tumour using callipers.
Start treatment.
Follow tumour volume over treatment.
48
Q

How does in vivo bioluminescent imaging work?

A

Implant luc+ cells in immune deficient mice.
Wait for tumour formation.
Measure luminescence with CCD camera.
Start treatment.
Make real time luminescence measurements.

49
Q

What are the advantages and disadvantages of the conventional approach to in vivo models?

A

Well established methodology.
Measures actual tumour size.
Needs many animals and is very invasive.

50
Q

What are the advantages and disadvantages of the in vivo bioluminescent imaging approach?

A

Less animals, detect smaller tumours.
Can make multiple real time measurements.
Possibility for indirect effects on luciferase.

51
Q

What are the pros and cons of genetically engineered mouse models for in vivo studies?

A

Provide more realistic tumour models, often spontaneously arising in a microenvironment.
They can be much more difficult to establish.

52
Q

What determines if a new agent is effective?

A

Does the agent reduce tumour size?
Does the agent prolong survival or increase time to relapse?
Does the agent improve on current therapy?
Does the agent improve quality of life.

53
Q

What determines the safety profile of a new agent?

A

What are the major side effects?
What is the maximum tolerated dose.

(The question, “what is the most biologically effective dose?” is not usually integral)

54
Q

What are the objectives and endpoints of phase 1 clinical trials?

A

Objective: determine safety, toxicity and dosage.
Std design: patients refractory to std therapy, dose escalation, various tumours
Primary endpoints: toxicities, maximum tolerated dose, pharmocokinetics.
Secondary endpoints: pharacodynamics, preliminary evidence of tumour response.

55
Q

How many patients take part in phase 1 clinical trials?

A

10-30

56
Q

What are the objectives and endpoints of phase 2 clinical trials?

A

Determine evidence of efficacy
• Std design: single arm, single dose (MTD), single tumour types, historical control
– 1y endpoints: Objective radiologic response, time-to-progression
– 2y endpoint: safety, pharmacodynamics

57
Q

What are the objectives and endpoints of phase 3 clinical trials?

A

Determine overall treatment benefits
• Std design: multi-centre, multi-arm (standard therapy control), randomised &
blinded, single dose, single tumour types
– 1y endpoints: Progression free survival, overall survival benefit
– 2y endpoints: Determinants of efficacy

58
Q

How many patients usually take part in phase 2 clinical trial?

A

30-300

59
Q

How many patients usually take part in phase 3 clinical trial?

A

300-3000

60
Q

What are the key trial design issues in each phase?

A

1: - patients refractory to therapy
- different tumour types
- focus on MTD, not effective dose.

2: - no investigation of dose response
- usually no control group
- OR ignores disease stabilisation.

3: - overally survival may not take account of second or third line therapies.

Cancer (11 decks)

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