Chem590A_JAK - Pharmacogenomics Tailoring Drugs to Fit...

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Pharmacogenomics: Tailoring Drugs to Fit Individual Human Genotypes: Classical Examples and Modern Approaches John A. Katzenellenbogen University of Illinois Chem 590A Fall, 2005 I. Pharmacogenetics and Pharmacogenomics II. Receptors and Signal Transduction Pathways III. Nuclear Hormone Receptors IV. Rudiments of Pharmacology: potency, efficacy agonism, antagonism, inverse agonism, etc.
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Pharmacogenetics and Pharmacogenomics: An Example – TPMT N N N N SH Mercaptopurine - Leukemia drug [Active form - also toxic] H N N N N S H Me TPMT TPMT = Thiopurine Methyl Transferase Inactive Drug form Human Population: 90% high TPMT – rapidly inactivate the drug; need high dose to be effective 10% intermediate TPMT – inactivate drug more slowly; lower dose works 0.3% no TPMT – very little drug inactivation; high danger of toxicity
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Pharmacogenetics and Pharmacogenomics: An Example – TPMT
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Pharmacogenetics and Pharmacogenomics: An Example – TPMT
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Pharmacogenetics and Pharmacogenomics: An Example – TPMT If you genotype patients, you can identify wt/wt, wt/m, and m/m patients Dose can be adjusted to give equivalent exposure and equivalent desired effect, with comparable toxic side effects Without genotyping, the m/m patients will die and the wt/m patients will experience excessive toxicity
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Pharmacogenetics and Pharmacogenomics
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Pharmacogenetics and Pharmacogenomics:
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Summary of Pharmacogenetics/omics Change in —— Drug Metabolism or Clearance Faster - use more drug Slower - use less drug Drug Target – altered Lower affinity - use more drug Higher affinity - use less drug Absent all together - look for another target; alternate therapy
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I. Pharmacogenetics and Pharmacogenomics II. Receptors and Signal Transduction Pathways III. Nuclear Hormone Receptors IV. Rudiments of Pharmacology: potency, efficacy agonism, antagonism, inverse agonism, etc. Lecture Outline
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Taken from Lodish
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Taken from Lodish
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Lecture Outline I. Pharmacogenetics and Pharmacogenomics II. Receptors and Signal Transduction Pathways III. Nuclear Hormone Receptors IV. Rudiments of Pharmacology: potency, efficacy agonism, antagonism, inverse agonism, etc.
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Nuclear Receptors: Versatile Targets for Pharmaceutical Action Nuclear Receptor Structure – Ligand Control of Conformation and Interactions Estrogen Receptor Ligand Synthesis – ER α and ER β Subtype Selective Ligands Reengineering of Ligand-Receptor Specificity – Estrogen-Androgen Orthogonal Ligand Receptor Specificities Human Mutants of Nuclear Receptors – Designing Ligands for Mutant Receptors - John Koh
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Receptor Histone, Factor acetylation CBP/p300 P/CAF SRC Pol II TBP basal factors L L Nucleus Chromatin Ligand/SERM TATA RE RE Cytoplasm L L Receptor-Mediated Gene Activation
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This note was uploaded on 12/04/2011 for the course CHEM 590A taught by Professor Staff during the Summer '10 term at University of Illinois, Urbana Champaign.

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Chem590A_JAK - Pharmacogenomics Tailoring Drugs to Fit...

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