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

  • Bioorg Med Chem Lett. 2006 Aug 15;16(16):4272-8. doi: 10.1016/j.bmcl.2006.05.065.
Sachin Mahale  1 ,  Carine Aubry ,  A James Wilson ,  Paul R Jenkins ,  Jean-Didier Maréchal ,  Michael J Sutcliffe ,  Bhabatosh Chaudhuri
Affiliations
  • 1. Leicester School of Pharmacy, De Montfort University, UK.
PMID: 16750360 DOI: 10.1016/j.bmcl.2006.05.065
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.