Drug Discovery and Development in the Post-Genomics Era

1. Drug Discovery and Development in the Post-Genomics Era Deanna L. Kroetz, Ph.D. Department of Biopharmaceutical Sciences University of California San Francisco

2. DRUG DEVELOPMENT PIPELINE PRE-CLINICAL DRUG EVALUATION CLINICAL TRIALS THERAPEUTIC USE DISCOVERY

3. HUMAN GENOME PROJECT • 3.2 Gbases (5% encode genes) • 32,000 genes (22,000 on list right now) • 15,000 known genes and 17,000 predicted genes • 6000 gaps to fill in • 971 known disease genes (e.g., Huntington’s Gene) • 500 known genes encoding drug targets • 1 in 1000 bp differences between us • 1 in 100 bp differences between us and a gorilla

4. Pharmacogenomics and Pharmacogenetics: Impact on Drug Discovery and Development

5. DRUG DISCOVERY • IDENTIFY A DISEASE: High Blood Pressure • IDENTIFY A TARGET: Calcium Channel • TEST POTENTIAL DRUG CANDIDATES

6. Impact of Genetics/Genomics on Drug Discovery • Mining genetic sequence databases • Monitoring gene expression patterns during disease/drug treatment • Model organisms

7. PARALOGS OF COMMON DRUG TARGETS IDENTIFIED BY SEARCHING DRAFT HUMAN GENOME TARGETHGM CHR. No.PARALOG CHR. No. IDENTITY SYMBOL % Calcium ChannelCACNG2 11CTG17137 12 70 DopamineDRD1 5CTG25203 16 71 Receptor **NATURE, VOLUME 427, TABLE 27, PAGE 913

8. HER2 Gene Product is Overexpressed in One Third of Breast Cancers • TUMOR OVEREXPRESSING HER2 • SENSITIVE TOHERCEPTIN

9. Goal: Tailoring New Drugs to Target Different Types of Breast Cancer • TUMOR OVEREXPRESSING ? • SENSITIVE TO ??? • TUMOR OVEREXPRESSING HER2 • SENSITIVE TO HERCEPTIN • TUMOR OVEREXPRESSING ?? • SENSITIVE TO???

11. Fluoxetine-Induced Phenotype in C. Elegans - Fluoxetine + Fluoxetine Choy and Thomas Mol. Cell 4:143, 1999

12. Fluoxetine Resistant Mutants Choy and Thomas Mol. Cell 4:143, 1999

13. Identification of Novel Membrane Transporters Choy and Thomas Mol. Cell 4:143, 1999

14. Impact of Genomics on Drug Development • Differentiate responders from non-responders • SNP mapping in clinical trials and drug surveillance • Genotyping for metabolism and transport polymorphisms affecting pharmacokinetics and pharmacodynamics

15. HER2 + HER2 - Differentiate Responders from Non-responders: HER2 Herceptin Breast Tissue Biopsy Other Drugs

16. SNP Maps

17. SNP Mapping In Clinical Trials Patients withefficacy Patients withoutefficacy Predictive of efficacy Predictive of noefficacy Adapted from Roses Nature 405:857, 2000

18. SNP Mapping in Clinical Trials and Surveillance Research Phase II Clinical Trials Smaller, faster and more efficient Phase III trials Market approval with medicine response profile; pharmacogenetic surveillance Enhancement with comprehensive medicine response profile; traditional surveillance Adapted from Roses Nature 405:857, 2000

19. Genetic Variation in Drug Response Genes • Drug Metabolizing Enzymes Cytochromes P450 Thiopurine Methyltransferase N-Acetyl transferases • Drug Targets b2 Adrenergic Receptor Dopamine Receptor • Drug Transporters

20. Pharmacogenetic Mapping In Clinical Trials CYP2C19 MDR1 CYP2C9 CYP2D6 b2AR Patients withefficacy *1 *1 *1/3 *1/2 *1/2 Patients withoutefficacy *1 *2 *1/3 *1/2 *1/2 CYP2C19 CYP2C9 MDR1 CYP2D6 b2AR Patients without toxicity *1 *1/2 *1 *1/2 *1 Patients with toxicity *1 *1/2 *3 *1/2 *2

21. PHARMACOGENETICS OF MEMBRANE TRANSPORTERS PROJECT Kathy Giacomini, PI Ira Herskowitz, Co-PI University of California San Francisco

22. G T E N T 1 , E N T 2 N E T A 1 C N T 1 C N T 2 D A T S E R T O C T 1 O C T 2 O C T 3 P E P T 1 P E P T 2 D M T 1 C T R 1 M D R 1 M R P 1 M D R 2 M R P 2 B S E P Pharmacogenetics of Membrane Transporters + + N a G A B A N a N u c l e o s i d e N o r e p i n e p h r i n e + N a + N u c l e o s i d e N a D o p a m i n e + N a V M A T 1 N u c l e o s i d e V M A T 2 + V A C h T N a S e r o t o n i n O r g a n i c C a t i o n s U C S F P H A R M A C O G E N E T I C S O F M E M B R A N E T R A N S P O R T E R S + + + F e O l i g o p e p t i d e s + H + + C u H y d r o p h o b i c H y d r o p h o b i c C a t i o n s A n i o n s

23. Pharmacogenetics of Membrane Transporters • What is the genetic variation in the genes encoding membrane transporters in human populations? • What is the functional significance of the variant transporters in heterologous expression systems? • How does genetic variation in membrane transporters affect clinical drug response?

24. Percent Frequency of Non-synonymous Coding Region SNPs FREQUENCY OF SNPs % TRANSPORTER SERT MDR1 ~1 >40

25. MDR1 Variants 49 Variants 3 non-coding 20 coding 26 intronic 7 synonymous 13 non-synonymous

26. P-glycoprotein Functions as a Drug Efflux Pump Apical side Basal side

27. Bioavailability CNS Exposure Drug Efficacy and Toxicity Clinical Significance of P-gp Polymorphisms

30. THE HUMAN GENOME http://www.nature.com (pages 814-958) www.sciencegenomics.org

31. Breast Cancer LATER STAGE EARLY STAGE

32. PHARMACOGENOMICS: The use of genetics and genomics in drug discovery and development • PHARMACOGENETICS: Genetic basis for differences in drug response