1. Chemical Genomics – Biol503 Lecture 2 Chemical Genomics and cancer/cardiovascular diseases

2. Anticancer Drug Screen

3. Traditional Approach: cell growth inhibition Screen of synthetic and natural product compound libraries for inhibitor of cancer cell-lines NCI’s cancer cell-lines (free) NCI’s Open Chemical Repository Collection (140,000 compounds) NCI’s Natural Products Repository

4. Protein Kinases – cancer and cardiovascular diseases

5. Cancer Pathways – cellular targets Source: Prous Integrity

6. Phosphorylation Phosphorylation by protein kinases is the most widespread and well-studied signal mechanisms in eukaryotic cells Kinome: 518 kinases, each phosporylates a distinct set of substrates Understanding complex network of kinase-based signaling is important for cancer and cardiovascular diseases

7. Kinase assay – an example Time resolved FRET

8. Approved drug: an example Tykerb (lapatinib ditosylate) is an EGFR and ErbB-2 dual tyrosince kinase inhibitor. EGFR- epidermal growth factor receptor ErbB-2 (HER2/neu) – Human Epidermal growth factor Receptor 2 Developed by GlaxoSmithKline Approved by FDA March 2007 for use in combination with capectabine for patients with advanced, metastatic breast cancer that is HER2 positive.

9. Protein Tyrosine Phosphatases – cancer and cardiovascular diseases

10. Protein tyrosince phosphatases The PTP superfamily of enzymes functions in a coordinated manner with protein tyrosine kinases to control signal pathways Regulatory role of protein kinases well established. But protein phosphatases can no longer viewed as passive housekeeping enzymes in the processes.

11. Diversity of PTPs

12. Regulation by dimerization

13. Regulation by Ligands

14. PTPs and Cancers

15. ProFluor Assay

16. References Johnson and Hunter, Nature Methods, 2005 N.K. Tonks, Nature Review Mol Cell Biol, 2006