molecular medicine. focus on cancer most chemotherapies were developed before the human genome was...
Post on 21-Dec-2015
216 views
TRANSCRIPT
Focus on Cancer
• Most chemotherapies were developed before the human genome was sequenced
• Many are alkylating agents that attach methyl groups.
• Derived from accidental explosion on ship that released alkylating agent and caused leukopenia or fewer white blood cells.
• When leukemia was observed to have too many white blood cells, they thought that alkylating agents might work
Rational Drug Design
• Instead of random chance or exhaustive search through all chemical compounds
• Chronic myelogenous leukemia (CML) comes from myeloid cells in bone marrow
• After 3 or 4 years, white blood cells increase and finally result in a blast crisis
• During Mitosis, chromosomes can be observed under the microscope and they noticed a translocation of a region from chromosome 9 with a region on chromosome 22
Philadelphia Chromosome
• Generate embrionic cells
• Ableson virus cariesends of the murine leukemia virus
• Translocation brings together BCR and ABL
Tyrosine Kinase
• There were probably a number of other translocations that resulted in cell death.
• This translocation resulted in uncontrolled growth and so is more dominant
Aggressive Cancer
• The translocation interferes with apoptosis• The lack of apoptosis when cell damage
occurs leads to further mutation
Tyrosine Kinases
• There are 90 tyrosine Kinases in the human genome
• A drug should be specific to the BCR-ABL Tyrosine Kinase
Tyrosine kinase
• All 90 versions of Tyrosine kinases have very similar catalytic clefts
• You don’t want to interfere with other tyrosine kinase proteins
• You want the drug to bind tightly to BCR-ABL so dosage is low
• Want a drug that stays around and is not metabolized
What about Metabolism
• CML cells implode if BCR-ABL doesn’t fire.• BCR-ABL provides anti-apoptopic signal as well
as growth factor• You have to shut down BCR-ABL for 12-15
hours for apoptosis to occur• Some people metabolize a drug more quickly
than others so a concentration necessary for 97% of the population may kill the other 3%
Gleevec• Drugs cost $1B to develop and get through the
clinical trials• 10,000 new cases of CML occur in USA and
Europe every year• Gleevec binds to active site of 3/90 TK– BCR-ABL shuts down at lower concentrations than
EGF-R Tyrosine Kinase so it can be dosed to be specific• 96% of patients were cytologically (microscope)
cured• Even in these patients, the BCR-ABL translocation
could still be detected in patients with PCR
Long Term
• 10-12% of patients relapse every year• The relapsed patients cancer cells have
mutations in BCR-ABL that keep Gleevec from binding
• So, now you need a new drug to treat mutants