modern Flashcards
what kind of cells do chemotherapy target?
highly proliferating cells and then their process like cell cycle
what are the approaches for targeting only cancer cells?
- We can identify individual pathways that are aberrant in the cancer cell but not in the normal cell
- We can identify targets that are expressed/over-expressed in the cancer cell that are not expressed in the normal cell.
what mutation may women have that may result in them having a significantly higher risk of developing breast and/or ovarian cancer in their lifetime?
BRCA1 and BRCA2
what does BRCA1 do?
part of our double strand break repair machinery and binds to RAD51 to help identify mutations.
what happens when BRCA1 has a mutation?
it won’t repair the double strand break so we lose the repair, resulting in cell death of misread DNA and translocations and mutations
what is personalised medicine?
Move away from the “one size fits all approach”
Moving closer to more precise, predictable and powerful medicine – customised for the individual patient
Growing understanding of genetics is allowing better diagnoses, safer drug prescribing and more effective treatments
what does personalised medicine classify tumours according to?
their genetic make-up instead of where they grow in the body
what are the benefit of personalised medicine?
Drugs are often tested on broad populations and prescribed using statistical averages
what are some aims for personalised medicines?
- Shift the emphasis in medicine from reaction to prevention
- Predict susceptibility to disease, improve disease detection, pre-empt disease progression
- Customize disease-prevention strategies
- Prescribe more effective drugs and avoid prescribing drugs with predictable side effects
- Reduce the time, cost, and failure rate of pharmaceutical clinical trials
- Eliminate trial-and-error inefficiencies that inflate health care costs and undermine patient care
what is the name of the enzyme involved in DNA repair, it is an inhibitor?
Poly(ADP)ribose polymerase or PARP
what do PARP do?
-they repair DNA form duplex DNA
what does PARP inhibitors do?
result in the formation of a double strand DNA break as the sing strand break isnt repaired and is replicated
what does BRCA1 and 2 do?
prevent repair of double strand breaks
what is BRAF mutation?
common in melanoma
WHAT IS THE PROTEIN-PROTEIN INTERACTIONS?
An interaction of two proteins at their domain interfaces that regulates
the function of the protein complex
what is the domain intefaces?
is the part of a protein that can function and exist
independently from the rest of the protein
why do we want to target PPIs?
- molecular target driven
- many cellular processes involve PPI
- Understanding of how proteins engage and communicate
- understand how Human diseases can be caused by irregular PPI’s
what are some potential problem of PPI?
-often referred to as “undruggable”
-Affinity achieved from the accumulation of numerous weak interactions
-Hydrophobic nature results in drug leads that
are large and hydrophobic can be had for oral doseage
how to target protein-protein interaction?
-fragment base drug discovery
what are the BCL-2 family?
- B-Cell Lymphoma-2 Family (BCL-2)
- Key regulators in cell apoptosis
what does altering the balance of BCL-2 proteins do?
altering the balance of the pro survival and pro death provides one means by which cancer cells undermine
normal apoptosis
what type of BCL-2 gene are over expressed in cancer?
the pro survival ones which increases the apoptosis threshold therefore preventing apoptosis
how do pro death BCL-2 proteins work to result in apoptosis?
-pro death proteins BAK/BAX have activators that bind to the pro death protein to activate them resulting in MOMP forming holds in mitochondria
how do pro survival BCL-2 proteins work to result in apoptosis?
-the pro survival proteins bind to activator proteins and pro death preventing them from binding together
how do pro death BCL-2 proteins work to result in apoptosis?
when cell death signals come, sensitiser bind to pro survival protein that free up activator for pro death leading to apoptosis
how does cancer cells benefit from pro survival?
cancer keeps up regulating pro survival even when there are death signals
what does P53 do?
its the guardian of the genome
- apoptosis
- blocks angiogenesis
- cell cycle arrest
- DNA repair
how is P53 avoided in human cancers?
- it has a mutation so it can bind to DNA
- up regulation of other proteins to prevent it from getting close to DNA like MDM2
- is inactivated by several viral proteins
what does MDM2 do?
MDM2 binds to P53 and stops it from finding DNA?
how does MDM2 PRVENT P53 FROM WORKING?
-over express MDM2 and P53 is unable to get into the nucleus leading to proliferation?
how does P53 bind to MDM2?
Binding site on MDM2: deep, hydrophobic groove p53 binds in an -helical conformation Forms 3 critical contacts through the side chains of Phe19, Trp23, Leu26 (hot spots) 300 Å2 Backbone of p53: no interaction except for 1 H-bond scaffold for the side chains
how do the nutlins work?
- they displace P53 from MDM2
- Mimics the interactions of p53
what are some possible plans to target PPIs?
Identify a peptide that will mimic a crucial peptide binding region for
one of the proteins
why are peptides not good drugs?
BUT peptides are not good drugs – poor metabolic stability and low
bioavailability
what is a method that can be done to alter peptides to make them better drugs?
- peptide stapling
- photo
how does peptide stapling work?
takes long chain and connects the staples along back bone to bring it closer in on its self into a helic
how does photodynamic therapy work?
light come towards our our photosensitiser and changed oxygen into single atoms with lead to cell death -Non-invasive -Minimal side effects - Only activated in irradiated cells
what does gold nanoparticles take advantage of for delivery?
the fact that the blood vessels are leaky due to enhanced permeability and retention effect
