Download molecular-medicine

Molecular Medicine
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
Response to drug concentration
% BCR-ABLE
-8
-7
-6
-5
Log drug cocncentration
-4
-3
-2
-1
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%
Drug Concentration
Drug
Concentration
Time
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
CYP2D6 gene and metabolism