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PHAR 300 > drug development > Flashcards

drug development Flashcards

1
Q

what is said to be different for drugs and treatments in the future?

A
  1. There will be a lot more personalized therapy
  2. The kinds of drugs that we can anticipate will not always be chemical entities: they’ll include antibodies
  3. The new treatments for cancer will be better (more personalized to patient’s specific tumor mutation),
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2
Q

drug discovery starts with ________

A

research

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3
Q

research is usually done where?

A

university laboratories and drug companies

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4
Q

what is pathological research?

A

research basic problems, abnormalities behind diseases

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5
Q

what is Pharmacological research?

A

how certain drugs and potential drugs can modify the course of a disease

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6
Q

why is the cost per new discovered drug increasing?

A

all “easy” drugs have been discovered, and now more challenging diseases are being researched.

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7
Q

what is Alzheimer’s disease and what characterizes it?

A
  • progressive impairment of cognitive function
  • deposition of amyloid plaques in the brain which are associated with the destruction of the brain
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8
Q

why do we not yet have a good treatment for Alzheimer’s?

A

We do not know the basic pathophysiology or pathogenesis = it is very hard to develop an effective drug

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9
Q

what is Aducanumab and is it effective? why or why not?

A
  • monoclonal antibody) that removes amyloid fibers via immune system before the plaques are made
  • theoretically should prevent the destruction of neurons and microglia in Alzheimer’s
  • evidence is minimal and not very effective
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10
Q

Why are drugs rejected in clinical testing?

A
  • toxicity in animals.
  • because of high costs.
  • mains reasons are: pharmacokinetics and a lack of efficacy
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11
Q

are antibiotics profitable for pharm companies?

A

no since they are only sold for a couple of weeks

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12
Q

which are the top 3 drugs that make the highest profit?

A
  1. drugs for inflammatory conditions
  2. diabetes
  3. cancer drugs
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13
Q

what is preclinical research and what do we look for?

A

before giving drug to humans, we must look at basic pharmacology & toxicology to know if it works & what the risks associated are

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14
Q

who usually funds basic research, translational research, and clinical research?

A
  • Government does most of the funding of basic research (done mostly in university and government labs) and some of the initial translational research in models.
  • Industries (PhRMA member companies) do almost all the clinical research (testing in humans).
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15
Q

what is the process for basic research to develop a new drug?

A
  • trying to understand the pathogenesis of the disorder under study
  • find a target (could be a ligand-gated ion channel, an enzyme, a GPCR, etc. Most often they are receptors and enzymes)
  • try to develop a drug to hit it
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16
Q

current drugs usually target what?

A

enzymes and receptors

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17
Q

what are reasons for failure of drug development (even after identifying drug target)?

A
  • inefficacy
  • or unexpected side effects due to multiple control pathways in the human body that interact (non-selectivity)
  • Other drug targets unaccounted for can be involved in producing the same effect as your drug’s target (alternative ways for cells to produce disease effects, so your drug will not work).
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18
Q

What is gene therapy?

A

viral vector carrying a new gene gets into the cell and this new gene is inserted into the nucleus, and this gene encodes a protein that is missing in a particular disease, so the protein is ultimately made in the cell.

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19
Q

What characterizes cystic fibrosis and what new technique was used to treat it?

A
  • People with this disease are unable to make a particular chloride channel which causes mucus buildup in the lungs.
  • gene therapy
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20
Q

How can genomics be used to find drug targets?

A

We’re trying to figure out the genetic vulnerabilities of people with a particular disorder: comparing the control vs. disease population and seeing what the genetic differences are

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21
Q

What was the first success for gene therapy?

A

replacement of mutated Sickle-cell/Thalassemia genes with normal RBC gene via CRISPR to produce normal RBCs

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22
Q

We wish to develop targeted care for each person based on _________ and _____________.

A
  • pharmacogenomics
  • their risks for side effects
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23
Q

What is the pregenomic vs genomic therapeutic strategy?

A
  • Pregenomics: disease description, uniform disease, patient homogeneity, universal
    therapeutic strategy.
  • Genomics: disease mechanism, disease heterogeneity, individual variation, patient risk profiling,
    pharmacogenomics, and targeted care.
24
Q

Why should we measure gene expression in a person?

A
  • What happens in environmentally caused problems in terms of gene expression?
  • Response to stimuli: environmental changes (like drugs or disease) often cause changes in
    expression.
  • Disease markers and drug targets: changes in expression associated with disease can be
    diagnostic markers and/or suggest novel pharmaceutical approaches.
25
Q

Why is Bioinformatics an important field?

A

as it allows us to analyze data obtained from microarrays and other small-scale experiments that humans cannot manually analyze.

26
Q

What is microarray technology?

A
  • DNA complementary to genes of interest is generated and laid out in microscopic quantities on solid surfaces at defined positions
  • DNA from samples is eluted over surface-complementary DNA binds
  • Presence of bound DNA is detected by fluorescence following laser excitation
27
Q

What is functional genomics and it’s role in drug discovery?

A
  • understand the functions of various genes
  • we can study whether targeting a particular gene product will be useful in the development of our new drug.
28
Q

How has proteomics helped with drug discovery?

A
  • Has helped in prognosis, diagnosis, and knowing what drugs to use in some problems, in developing new molecular targets.
  • Allowed better ways of monitoring whether the drug is working or not in clinical trials and we can study normal cells, tumor cells, etc.
29
Q

What are ways to validate targets ahead of time?

A

studying these targets in vitro, in the animal model, in humans, and time-lapse images of what’s happening to tumors in people.

30
Q

What is the idea behind finding a ligand that binds to the target?

A

goal is to model a chemical after a natural ligand that will fit into the target. Targets are most often enzymes.

31
Q

How can combinatorial chemistry be used to find a molecule that binds to the target?

A
  • Combinatorial chemistry allows us to quickly develop and synthesize thousands of chemical compounds.
  • The large assortment of chemical compounds you develop in
    combinatorial chemistry are put into a test system in order to determine which compounds bind to the target of interest.
  • Combinatorial chemistry allows to put together different parts of molecules from combinatorial libraries to create thousands of similar compounds that may differ only in a section, and they must be tested quickly.
32
Q

_________________ is used to test the thousands of compounds made in combinatorial chemistry and takes much less time than __________

A
  • High throughput screening
  • manual screening
33
Q

Combinatorial chemistry is done in _____, and then you move along to in ____ studies

A
  • vitro
  • vivo
34
Q

What are ways to eliminate the drugs ahead of time that will not work?

A

Using mammalian cells, microbes (i.e., in the development of an antiviral drug), microsomal enzymes (i.e., isolating P450 enzymes from the liver), synthetic membranes, cell-based assays or cell-free assays.

35
Q

Responses (i.e., between the compound of interest and an enzyme) can be quantified with what?

A

fluorescence, luminescence, enzymatic, radioactive, immunological

36
Q

What is a way to identify ligands using mass spectrometry?

A

combining your target protein in vitro with a mixture of potential ligands. Then, wash this solution such that only the ligands that bind to the target protein are present. And then you can release the bound compounds and run them through mass spectrometry in order to identify which ligands have bound to the target protein. It can be a lead compound that you can play around with to get a more specific compound.

37
Q

What is an animals model that has been highly used?

A

Zebrafish

38
Q

What are things high throughput screening cannot evaluate?

A
  • Bioavailability (the amount of drug that will get to the rest of the body after the first-pass effect)
  • Pharmacokinetics: you cannot tell the absorption fraction or how much of the drug will be
    distributed across various membranes
  • Toxicity of the drug
  • Mutagenicity: Is there a possibility that the drug will develop into a mutagen after it’s absorbed?
  • Specificity of the drug: we cannot determine side effects until the drug is tested in living systems
39
Q

What is a way to detect mutagenicity?

A

Using yeast cells:
- have DNA repair genes, which are
expressed in response to mutagens that induce damage to DNA.
- The DNA repair genes can be coupled with luciferase, so you see green fluorescence when these
genes are activated by mutagens.
- Thus, you can detect DNA damage

40
Q

What is a way you can test for drugs that affect chemotaxis and metastasis?

A
  • you can run an experiment in which there is some chemotactic factor on one side of the filter that draws the cells from one side of the filter to the other.
  • Then, you can test a drug that is designed to block the mobility of cancer cells. (Blocking mobility of cancer cells could be very effective in treating cancer, because tumors
    wouldn’t be able to metastasize.)
  • Basically, this test allows you to see what compounds can cause metastasis and which compounds could block it
41
Q

How is computational chemistry used in drug discovery?

A
  • Calculations to tell us what sense we can make from what we got with combinatorial chemistry.
  • Studying the features of a receptor once it’s been identified as a target.
  • This can tell you ahead of time how to model a potential drug that will bind to this target receptor.
  • Software systems use knowledge of enzymes to design new drug(s).
    (The software systems can model the geometry, hydrophobicity, and many other features of the new drug.)
42
Q

What is Ibrutinib (Imbruvica) and what was its discovery based on?

A
  • This drug blocks an enzyme that’s overexpressed in malignant B cells (in a type of chronic lymphocytic leukemia/CLL).
  • discovery was based on understanding the structure of the particular enzyme that was overexpressed and modeling a drug to block it
43
Q

What do statins do?

A

decrease the production and release of cholesterol from the liver.

44
Q

What do PCSK9 inhibitors do? What type of drug is it?

A
  • increases the number of receptors recycled back to the membrane to increase LDL clearance via binding to/inhibiting PCSK9
  • monoclonal antibody
45
Q

What is Biosimulation and why is it useful?

A
  • is a way of simulating pathogenesis and mechanisms of biological pathways implicated in diseases,
  • useful in drug discovery and minimizing the drug’s side effects. Can predict + and – effects.
46
Q

What are Strategies to avoid formation of anti-mouse antibodies?

A
  1. Chimeric antibodies (mouse variable region + human constant region)
  2. Primatized antibodies (chimeric with primate-derived variable region)
  3. Humanized antibodies (all human except antigen recognition site)
  4. Transgenic mouse antibodies: (fully humanized antibody)
47
Q

Monoclonal antibodies are being used to treat which types of diseases?

A

Autoimmune diseases

48
Q

How do Monoclonal antibodies for osteoporosis work?

A

are antibodies against osteoclasts, which break down bone, which slows down bone breakdown to give you more time to build bone up.

49
Q

For colorectal cancer, Monoclonal antibodies can be used to either…

A

Target the tumor itself, the microenvironment (surrounding the tumor), or the blood supply to the tumor (angiogenesis).

50
Q

Adalimumab is used to treat what?

A

treating autoimmune diseases. (rheumatoid arthritis, psoriasis, etc.) by Tumor Necrosis Factor (TNF) inhibition

51
Q

Preclinical evaluation usually involves which animal model?

A

Rats and mice

52
Q

Why are rats the classical animal model?

A

we know its detailed biology and we
can work out the pharmacodynamics (the detailed mechanism of action) and pharmacokinetics (bioavailability, single/multiple doses, male/female effect, pregnancies, look at different organs ex. Kidneys, etc.) of the new drug in the animal.

53
Q

For drugs that act on the brain, ______ are used usually

model organism

A

primates

54
Q

What is the Ames Test used for?

A

used to look for mutants and the DNA repair genes and luciferase test in yeast cells.

55
Q

Teratogen studies have to be done in ______ to see what happens to the fetus

A

rodents

56
Q

what is it we are looking for when developing a new drug?

A
  • 1⁄2 life to be reasonable such that we are not required to take the drug too often
  • also have reasonable costs
  • must know the therapeutic window (know the minimal dose and the toxic dose).
  • Ideally orally absorbed.
57
Q

what is the summary of the preliminary research and preclinical research?

A
  1. Find a drug target
  2. Find a lead molecule that interacts with the target
  3. Optimize the structure through repeated cycles of synthesis and testing
  4. Determine the pharmacodynamics, kinetics (ADMET – absorption, distribution, metabolism,
    excretion & toxicity), side effects and toxicity in animal models….
  5. Then file an application for a clinical trial.

PHAR 300 (12 decks)

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