Design, synthesis and biological evaluation of new tryptamine and tetrahydro-β-carboline-based selective inhibitors of CDK4

We present the design, synthesis and biological activity of a library of substituted (biphenylcarbonyl)-tryptamine and (biphenylcarbonyl)-tetrahydro-β-carboline compounds related to the natural product fascaplysin, as novel inhibitors of CDK4/cyclin D1. We show all these molecules, prepared using the Suzuki–Miyaura reaction, being selective inhibitors of CDK4 over CDK2. The most active compounds have a CDK4 IC50 in the range 9–11 μM, three of them containing the para-biphenyl plus para-substituents supporting the existence of a π-stacking pocket within the active site of CDK4.

A library of selective inhibitors of CDK4 based on a tryptamine or β-carboline biphenyl carbonyl amides have been synthesised using the Suzuki–Miyaura cross-coupling reaction. The compounds were designed in view an observed π-stacking pocket within the active site of a CDK4 homology model.Figure optionsDownload as PowerPoint slide