Transcript Slide 1
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