Molecular MedicineFocus on CancerRational Drug DesignPhiladelphia ChromosomeTyrosine KinaseAggressive CancerTyrosine KinasesTyrosine kinaseResponse to drug concentrationWhat about MetabolismDrug ConcentrationGleevecLong TermCYP2D6 gene and metabolismSlide 15Molecular MedicineFocus 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 workRational 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 22Philadelphia Chromosome•Generate embrionic cells•Ableson virus cariesends of the murine leukemia virus•Translocation brings together BCR and ABLTyrosine Kinase •There were probably a number of other translocations that resulted in cell death.•This translocation resulted in uncontrolled growth and so is more dominantAggressive Cancer•The translocation interferes with apoptosis•The lack of apoptosis when cell damage occurs leads to further mutationTyrosine Kinases•There are 90 tyrosine Kinases in the human genome•A drug should be specific to the BCR-ABL Tyrosine KinaseTyrosine 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 metabolizedResponse to drug concentration-8 -7 -6 -5 -4 -3 -2 -1Log drug cocncentration% BCR-ABLEWhat 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 ConcentrationTimeDrug ConcentrationGleevec•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 PCRLong 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 mutantsCYP2D6 gene and
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