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

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 IC50 ∼ 5.5 μM). As would be expected of a Cdk4 inhibitor that does not inhibit Cdk2, it maintains a G0/G1 block in synchronised cancer cells and inhibits Cdk4-specific phosphorylation of the retinoblastoma protein.

Graphical abstractCA224, a tryptamine analogue of fascaplysin, is a specific inhibitor of Cdk4-D1 against Cdk2-A in enzyme assays, blocks cancer cells at G0/G1 and prevents pRB hyperphosphorylation, but does not bind or intercalate DNA like fascaplysin.Figure optionsDownload full-size imageDownload as PowerPoint slide