Inhibition of cancer cell growth by cyclin dependent kinase 4 inhibitors synthesized based on the structure of fascaplysin

Abstract

Tryptamine derivatives, a new structural class of cyclin dependent kinase 4 inhibitors, have been identified during extensive biological screening of synthetic molecules. The molecules were synthesized based on the structure of fascaplysin, which is not only a specific inhibitor of the Cdk4-cyclin D1 enzyme but also a relatively toxic molecule, probably because it binds and intercalates DNA. Interestingly, the new structural analogues of fascaplysin do not interact or intercalate with double-stranded DNA, although they inhibit Cdk4-cyclin D1 specifically. We found that compound CA199 was the most potent molecule, showing at least 25-fold specificity towards Cdk4-cyclin D1 (IC50 for Cdk4-cyclin D1 = 20 microM, Cdk2 > 500 microM). CA199 inhibits the growth of different cancer cell lines at concentrations ranging from 10-40 microM. It blocks growth of asynchronous cells at G0/G1 in a retinoblastoma protein (pRb) dependent manner. Moreover, CA199 blocks growth only at early G1 in synchronised cells released from a mimosine-induced G1/S block. These observations are reminiscent of a true Cdk4 inhibitor.