CA224, a non-planar analogue of fascaplysin, inhibits Cdk4 but not Cdk2 and arrests cells at G0/G1 inhibiting pRB phosphorylation.

Abstract

Tryptamine derivatives, non-planar and potentially less toxic analogues of the anti-cancer agent fascaplysin, have been synthesised. They specifically inhibit Cdk4-D1 vis a vis Cdk2-A but, unlike fascaplysin, do not bind or intercalate DNA. CA224 is the most potent compound identified (Cdk4-D1 IC(50) approximately 5.5 microM). As would be expected of a Cdk4 inhibitor that does not inhibit Cdk2, it maintains a G(0)/G(1) block in synchronised cancer cells and inhibits Cdk4-specific phosphorylation of the retinoblastoma protein.

• Authors: Sachin Mahale, Carine Aubry, A James Wilson, Paul R Jenkins, Jean-Didier Maréchal, Michael J Sutcliffe, Bhabatosh Chaudhuri
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 16 Issue 16 Pg. 4272-8 (Aug 15 2006) ISSN: 0960-894X [Print] England
• PMID: 16750360 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biphenyl Compounds
• CA 224
• Indoles
• Retinoblastoma Protein
• fascaplysine
• DNA
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinase 4

Topics

• Antineoplastic Agents (pharmacology)
• Biphenyl Compounds (chemical synthesis, pharmacology)
• Chemistry, Pharmaceutical
• Cyclin-Dependent Kinase 2 (metabolism)
• Cyclin-Dependent Kinase 4 (metabolism)
• DNA (chemistry)
• Drug Design
• G1 Phase
• Indoles (chemical synthesis, chemistry, pharmacology)
• Inhibitory Concentration 50
• Models, Chemical
• Phosphorylation
• Resting Phase, Cell Cycle
• Retinoblastoma Protein (metabolism)