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

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Presentation transcript:

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

Anticancer Drug Screen

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

Protein Kinases – cancer and cardiovascular diseases

Cancer Pathways – cellular targets Source: Prous Integrity

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

Kinase assay – an example Time resolved FRET

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.

Protein Tyrosine Phosphatases – cancer and cardiovascular diseases

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.

Diversity of PTPs

Regulation by dimerization

Regulation by Ligands

PTPs and Cancers

ProFluor Assay

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