W8 Anticancer drugs ll Flashcards
What are protein kinases?
Why are they an important target for anticancer strategies?
Enzymes that phosphorylate specific amino acids in proteins → phosphorylation of proteins → regulate their functions→ modulation of signalling cascades→ control of transcription of specific genes in DNA→ cell growth and division
Regulation of these pathways impaired in many cancers: accelerate cell signalling cascades and cellular growth, induce tumours, and augment antiapoptotic processes
What are mutation hotspots?
Mutation hotspots are aberrations in protein phosphorylation by kinases that act as “drivers” of neoplastic disease. Patients are carefully screened for these genomic markers.
What cofactor do all kinases use as a phosphorylating agent?
What are the two key regions in the active site of a kinase?
=ATP
=The kinase active site has a region for ATP binding and a vicinal region where the substrate binds.
What are the Four different way of reversible binding/kinase inhibitors and their mechanisms?
- Type I inhibitors: compete with ATP and bind to the enzyme in its active form
- Type II inhibitors: bind to the inactive kinase conformer
- Type III molecules: fit into a binding pocket adjacent to the active site (allosteric binding)
- Type IV inhibitors: binding to allosteric binding site that is distant from the ATP-binding site
Where do most protein kinase inhibitors (KIs) bind, and what does this binding achieve?
Most KIs bind the hydrophobic hinge ATP cofactor region connecting the N-terminal and C-terminal lobes of the kinase, exhibiting surprising selectivity due to five potential binding pockets surrounding the ATP-binding pocket.
What are the 2 major challenges to KIs?
- Acquired resistance due to gene mutation, making kinases unresponsive to the drug (no longer bind/respond)
- Risk of drug-drug interactions with CYP/P-glycoprotein inhibitors or inducers, and drugs that raise gastric pH
What are two ongoing research goals for improving kinase inhibitors (KIs)?
What is the purpose of combination kinase inhibitor (KI) therapy?
- Designing more selective drugs to enhance effectiveness.
- Screening tumor cells for resistance mechanisms to create more robust therapies for mutation-adaptive neoplasms.
Combination KI therapy targets specific or parallel kinase pathways, or crucial tumor cell properties, to delay or overcome resistance.
Name key kinases targeted by protein kinase inhibitors (KIs)?
BCR-ABL
EGFR
ALK
HER2
VEGFR
BRAF
mTOR
Epidermal Growth Factor Receptor (EGFR) Inhibitors: What is an examples?
- Tyrosine kinase over-expressed or over-active in many cancer cells→ uncontrolled cellular proliferation and tumour development
Gefitinib (Iressa): potent EGFR-TK inhibitors for non-small cell lung cancer that has spread into the surrounding tissues or to other parts of the body
How Gefitinib was designed:
4-Anilinoquinazoline was identified as an important
pharmacophore for EGFR tyrosine kinase inhibition
Bioisostere approach: replace metabolically
susceptible groups with atoms of a similar size. F is a good bioisostere of H. Cl is a good
bioisostere of CH3.
- In silico studies: suggested space for expansion.
- May not bind significantly to protein, but could improve physical properties (e.g. solubility, logP) or pharmacokinetics (e.g metabolism, plasma half-life)
Many analogues were synthesized, and inhibitory activity given (IC50 µM) and extent of metabolism was measured as % drug in plasma after six hours
Gefitinib- Functional groups significance:
F and Cl = Block oxidative metabolism and bind in hydrophobic pocket
H = H bonding
MeO and O = EDGs
Ring with O and N = Increases plasma half life and confers good aqueous solubility
DNA Repair – A new target for cancer therapy:
What events can damage DNA?
Why is this important?
What do healthy cells do to defend themselves against DNA?
Cellular respiration, Sunshine (UV light), Cigarette smoke, Car exhaust, Burnt food (around 10,000 events per day per cell)
DNA damage and its repair or lack thereof: central to the induction of mutations→ development of nearly all cancers
Healthy cells: defend themselves against DNA damage through the DNA damage response (DDR) →recognise DNA damage→ stall the cell cycle→ mediate DNA repair→ maintaining the integrity of the genome
What is synthetic lethality?
- Synthetic lethality is defined by cellular or organismal lethality caused by combined alterations of gene pairs that are otherwise individually viable (non-lethal)
- Synthetic lethal genetic interactions with tumour-specific mutations may be exploited to develop new anticancer therapeutics
PARP inhibitors: an example of synthetic lethality
Poly(ADP-ribose) polymerase isozymes PARP1 and PARP2: repair DNA single-strand breaks or base excision
If PARP activity is inhibited, single-strand breaks progress to double-strand breaks, which will kill the cell
Cleaves Nicotinamide Adenine Dinucleotide
(NAD+) into nicotinamide and ADP-ribose→forms a protein bound polymer - a cellular signal for DNA repair→ PARP leaves, →final repair process by biochemical entities
that have been summoned to the scene by
the polymerized ADP-ribose
PARP inhibitors: an example of synthetic lethality
Breast and ovarian tissue: PARP and BRCA1/BRCA2 (tumour suppressors) repair
system
o Ovarian and breast cancers are often deficient in BRCA1/2
o Women with BRCA gene faults have a 45-90% chance of developing breast cancer
o IF PARP IS INHIBITED IN THESE CELLS, DNA repair is not possible, → cancerous cell will die. Synthetic lethality (healthy cell can still use BRCA1/2)
