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week 8 part 2 Flashcards

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1
Q

Why do most compounds not become medicines?

A
  1. complex disease targets
  2. Too long in the body
  3. Adverse reactions
  4. Poor Absorption
  5. Low levels in the body
  6. Not effective enough
  7. Not sufficiently selective
  8. Side effects
  9. Unsafe
  10. Unstable
  11. Competition
  12. Impractical to make
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2
Q

What is pharmacogenomics?

A

The application of genomic technologies such as gene sequencing, statistical genetics, gene expression analysis to drugs in the clinical development and on the market

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3
Q

What does pharmacogenomics apply to?

A

large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism, or disease pathways.

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4
Q

What is the potential implication of pharmacogenomics in clinical research/medicine?

A

disease could be treated according to genetic and specific individual markers, selecting medications and dosages that are optimized for individual patients

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5
Q

What is the possibility of defining patient population genetically?

A

improve outcomes by predicting individual responses to drugs, and could improve safety and efficacy in therapeutic areas such as neuropsychiatry, cardiovascular medicine, endocrinology (diabetes and obesity) and oncology

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6
Q

Where does genetics and genomic fits in?

A

Its Important in target validation, you can use omics and genetics to identify and validate targets

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7
Q

in lead candidate stage where you are testing for molecule in animal model. what should you look for?

A

at evolutionary fidelity of animal model

does target in animal model predict action of that target in humans or have evolutionary events caused the function of that target to divergence in animals

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8
Q

What happens in phase I in humans?

A
  1. use expression data
  2. Pathway knowledge
  3. Anticipate common adverse events that is related to safety
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9
Q

What happens in phase II in humans?

A
  1. look at efficacy of drugs

2. Look at common variants

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10
Q

What is pharmacovigilance?

A

the practice of monitoring the effects of medical drugs after they have been licensed for use, especially in order to identify and evaluate previously unreported adverse reaction

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11
Q

Target ID and validation?

A

Identification of drug targets based on biological rationale and known small molecule tractibility

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12
Q

Hit and Lead ID

A

Configure and run high throughput screen to ID bioactive small molecules

identify drug-like lead molecules

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13
Q

Lead to Candidate

A

Medicinal chemistry to optimise lead properties

Back up lead

Evaluate drug pharmacology in preclinical model

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14
Q

Phase I

A

Evaluate clinical pharmacology of candidate drug in 20-100 healthy human volunteers

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15
Q

Phase II

A

Determine therapetuic dose

Evaluate drug efficacy to achieve POC

conducted in 100-200 patients

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16
Q

Phase III & Market

A

Large comparative study (compound vs placebo) in 1000s of patients to establish clinical benefit and safety

Drug launch and subsequent safety surveillenace

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17
Q

What is Target Validation?

A

Target validation is the process by which the predicted molecular target – for example protein or nucleic acid – of a small molecule is verified

ongoing process

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18
Q

What does Target Validation include?

A
  1. Determining structure-activity-relationship of small molecules
  2. Generating a drug-resistant mutant of presumed target
  3. knockdown or overexpression of presumed target
  4. Monitoring the known signalling systems downstream of presumed target
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19
Q

When can you say a target is validated?

A

when a drug has been working in the clinic safety and effectively for many years

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20
Q

What is a great example of target validation?

A

Cox-2

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21
Q

What is Cox-2?

A

Pain target

target of cox2 inhibitors

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22
Q

What is a dual inhibitor?

A

Aspirin

Work on Cox-1 and Cox-2

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23
Q

What showed great efficacy in pain?

A

Selective Cox-2 inhibitors

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24
Q

What is integral to target validation?

A

Population safety

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25
What is Cox-2 directly marketed in the US for pain?
Age related pain osteoarthritis
26
What was Cox-2 marketed as?
Tool for healthy life style
27
What are the 2 Cox enzymes?
Cox-1 and Cox-2 Exist in blood vessels in an equilibrium
28
What happens when you inhibit COX2?
Disrupt that equilibrium and it causes clumping of platelets make platelets much more easily coagulable it causes an increase in vascular events
29
What did they found out ?
Cox2 inhibitors had 50% of cardiovascular events than people that didnt take Cox2 inhibitors
30
When a drug described as safe?
At the right dose
31
What are the perspectives on target validation and safety?
1. Biology 2. Variation 3. Similarity 4. Tractability
32
What is biology?
1. Biological mechanism 2. Disease association 3. Tissue expression 4. Pathways
33
What is variation?
1. Genetic variation 2. Isoform/splicing 3. Epigenetics
34
What is similarity?
1. Orthology (animal models) | 2. Homology (off target effects)
35
What is tractability?
1. Druggable 2. Biopharmable 3. Other e.g. siRNA 4. Robust assay
36
What fits into the target discovery and validation?
1. Talking about genetics and genomics
37
What are some examples of validating targets?
1. Look at cell models - cancer cell models to see if a gene is differentially expressed in cancer 2. Clinical samples - RA - looking at synovium of arthritis patients to look at genes that are upregulated/downregulated 3. Look at animal models
38
What do you look for in a gene expression proteomics?
Altered expression in the disease state using genetics
39
What do we need to consider for a target?
Pathway context
40
What is a pathway in drug discovery?
A target in a linear pathway modulate that pathway downstream effect which is specific and predictable
41
What is the reason why many drugs have side effects and adverse effects or lacking efficacy?
Pathways are complex | knowledge of pathway is incomplete
42
What may a target acting as a single critical node control?
influence many processes
43
What can network interactions be?
Redundant
44
What can drugs interact with?
Multiple targets
45
What are a consequence of interaction with multiple targets?
Efficacy and safety
46
What are crucial considerations in drug discovery?
1. Pleiotropy | 2. Redundancy
47
Where is intervention easier in?
Simple pathways
48
What does crosstalk between pathways introduce?
Complications to aspect of drug actions
49
What may efficacy call for?
Combination of therapy or poly-pharmacology
50
Why are no drugs completely effective?
Complexity of biology
51
What is pathway: STITCH good for?
1. Simple interface - Add multiple genes - Identify interaction - Identify known drugs - Expand network
52
What is Pathway analysis: ENRICHR good for?
♣ This tool allows u to look for enrichments of pathways in a gene set and gives u drug disease activity
53
ENRICHR
1. Simple Interface - Add multiple genes - Transcription - Pathways - Ontology - Diseases - Drugs
54
What do we look for when doing pathway analysis?
Multi-omics 1. Different genomic platform 2. Gene expression genetics 3. Proteomics 4. Drug response data
55
What are the 3 Endotypes in Rheumatoid Arthritis Synvovium?
1. Fibroid 2. Myeloid 3. Lymphoid
56
Fibroid
1. Fibroid gene that doesn't have much inflammatory signal | 2. Plasma cells, B cells and T cells - don't have a lot of immune cells infiltrating the tissue
57
Myeloid
More immune cells infiltrating the tissue but is different to fibroid subtype
58
Lymphoid group
Most trackable subtype lots of plasma cells and b cells that are coming out of the blood into tissue forming ectopic lymphoid structures- lots of b-cells in the joints
59
What is effective in lymphoid subgroup
drugs called rituximab which targets CD20 which is b-cell receptor
60
What is an advantage of targeted clinical trial ?
higher response and therefore u could demonstrate efficacy of drug much more clearly and unequivocally
61
What is a powerful way of validating targets?
GWAS
62
What is one of the first successful GWAS for target validation ?
welcome trust case control consortium | study looked at 7 diseases
63
What are the 7 diseases that case control consortium study look at?
1. Coronary artery disease 2. Crohn's disease 3. Hypertension 4. Rheumatoid arthritis 5. Type 1 diabetes 6. Type 2 diabetes 7. chromosome
64
Where did coronary artery have a big signal in?
Chromosome 9
65
Where did RA and type 1 diabetes have a big signal in?
Chromosome 6
66
What is the HLA region?
♣ Both ra and type 1 diabetes have a signal in the same region of the genome
67
What is interesting about Chrons disease (IBS)?
1. Loads of associations
68
What is autophagy?
a process by which the cells clean up debris in the body
69
What does Crohn's disease have?
Defective autophagy phasethe gut is not cleaned up properly which causes iBS and inflammation
70
What has GWAS given us?
thousands of genetics susceptibility loci
71
What was observed in GWAS catalogue?
1. 800 publications of gene disease associations | 2. identified 991 disease genes based on genetics
72
Therapeutic opportunities from GWAS
15% of these genes would be druggable and 25% of genes are biopharmable
73
What does the database pharma projects have?
information about which targets that they worked on by companies
74
What was the associations with statins?
1. HMGCR 2. hypercholesterolemia 3. LDL cholesterol
75
What is statin target?
1. ♣ HMGCR | 2. associated with cholesterol level in genetics
76
What is SLC30A9?
transport associated with type2 diabetes
77
What association was found with hypertension?
NR3C2 | Na+ channel- this is associated with blood pressure
78
What is fludrocortisone ?
known agonist of this target and its indicating for cerebral salt wasting syndrome and a side effect of that drug is that it causes hypertension
79
What is variation in drug response mediated by?
1. Pharmacodynamics | 2. Pharmacokinetics
80
Pharmacodynamics
 Relationship between drug concentration and effect |  “what the drug does to the body”
81
Pharmacokinetics
 Study of drug Absorption, Distribution, Metabolism and Excretion  “what the body does to the drug”
82
What are critical determinants of efficacy and safety?
PK/PD properties
83
What are PK/PD properties mediated by?
10s-100s genes
84
What is pharmacogenetics?
study of genetic variation in these genes
85
What does different variant of the target cause?
Different drug activity
86
When does a target not bind to drug very well?
might get variants that mutate target binding site
87
What is Beta2 adrenergic receptor ?
target of formoterol in asthma – inhaled drug
88
most common most widely used drugs
they have high rates of incomplete efficacy
89
What are 2 areas of pharmacogenetics?
1. Efficacy 2. Adverse events looking at responders and non-responders
90
Ideally, what are drugs?
1. Given orally | 2. Gut absorbed
91
What is the liver?
Principal organ of drug metabolism, although every biological tissue has some ability to metabolise drugs
92
Where does drug pass through?
Liver into circulation | The percentage dose reaching the circulation is known as bioavailability
93
What is rate of metabolism?
Important determinant of duration and intensity of drug action
94
What is one of the biggest dietary effect on drug action?
Grapefruit juice
95
What is grapefruit juice?
potent inhibitor of cyp3a4 and other cyp aswell and these enzymes metabolize most drugs
96
Grapefruit kuice
Inhibitor of the intestinal cytochrome P-450 CYP3A4 which is responsible for the first-pass metabolism of many medications Inhibition of CYP3A4 elevates serum drug concentration e. g. 1. Lovastatin (cholesterol reducing) 2. Cyclosporine (Antibiotic) 3. Some antihistamine medications
97
What is a genetic cause of variation of drug action on metabolism?
CYPD26 polymorphism
98
Deletion of CYPD26
Poor metabolizer
99
What are most drugs?
will be poorly metabolized so youll be exposed to most drugs at higher dose
100
rapid metabolizer/ ultra rapid metabolizer
multiple copies of cyp2d6 and that means most drugs u take will be metabolized at a blink of an eye – don’t get good effect of doses – youll need higher doses
101
What is Avandia?
effective type 2 diabetic drug very similar to cox2 it was widely prescribed in us
102
Why PPARG agonist cause cardiac events?
1. Type II diabetes target 2. Nuclear hormone receptor 3. Highly expressed in adipocytes 4. Rosiglitaozne (Avandia) was a blockbuster for GSK
103
What are the target expression?
1. GTEX 2. EBI gene expression atlas 3. NCBI GEO
104
What are the characteristics animal models should have?
 Should closely reproduce the disease or condition under study  Should be an industry/academic accepted model  The data should be robust enough to be duplicated by a 3rd party  Should show statistical significance – feasible to use sufficiently large number of animals to demonstrate statistical significance
105
What was Monoclonal CD28 agonistic antibody (T-cell co-activator) developed as?
Drug for leukemia and rheumatoid arthritis
106
What should be considered when selecting animal species?
Selection pressure
107
What does preclinical studies in animal aim to accurately predict?
Drug action and safety in man
108
When are preclinical studies only valid?
when the function of the gene is equivalent (orthologous) between the model and man
109
What are 3 types of selection pressure?
1. Negative selection 2. Neutral selection 3. Positive selection
110
Negative selection
Deleterious mutations are selected against to conserve function
111
Neutral selection
Neutral mutations are unaffected by selection
112
Positive selection
Advantageous mutations are selected for. Positive selection is indicative of functional change
113
DGIdb
put a list of genes and it will tell you whether they are druggable or whether theres a drug that’s already been used for that gene
114
Lipinski's rule of 5
1. No more than 5 hydrogen bond donors 2. No more than 10 hydrogen bond acceptors 3. A molecular mass less than 500 daltons 4. An octanol-water partition coefficient [5] log P not greater than 5
115
Lead like rule of 3 (RO3)
MASS <300D H donors , < =3 H acceptors, < = 3 rotatable bonds
116
What is connectivity map?
Database developed in rodents in Boston They took 4 cancer cell lines And each of these cell lines in-vitro they exposed to separately to 3000 FDA approved drugs

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