Chemical Genomics – Biol503

Lecture 2Chemical 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