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

-8 -7 -6 -5 -4 -3 -2 -1Log drug cocncentration

% BCR-ABLE

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

Time

Drug Concentration

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