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

• Published in: Bioorganic chemistry 2006-10, Vol.34 (5), p.287-297
• Main Authors: Mahale, Sachin, Aubry, Carine, Jenkins, Paul R., Maréchal, Jean-Didier, Sutcliffe, Michael J., Chaudhuri, Bhabatosh
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer chemotherapeutics; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cyclin dependent kinases; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - chemistry; DNA - chemistry; DNA Topoisomerases, Type I - chemistry; DNA, Superhelical - chemistry; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Ethidium - chemistry; Flow Cytometry; G 0/G 1 arrest; Humans; Indoles - chemistry; Indoles - pharmacology; Nucleic Acid Conformation; Phosphorylation - drug effects; pRb phosphorylation; Retinoblastoma Protein - metabolism
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2006.06.004

CA199, a tryptamine analogue of fascaplysin, is a specific inhibitor of Cdk4-D1 in enzyme assays, blocks cancer cells at G 0/G 1 and prevents pRb hyperphosphorylation, but does not bind or intercalate DNA like fascaplysin. 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 (IC 50 for Cdk4-cyclin D1 = 20 μM, Cdk2 > 500 μM). CA199 inhibits the growth of different cancer cell lines at concentrations ranging from 10–40 μM. It blocks growth of asynchronous cells at G 0/G 1 in a retinoblastoma protein (pRb) dependent manner. Moreover, CA199 blocks growth only at early G 1 in synchronised cells released from a mimosine-induced G 1/S block. These observations are reminiscent of a true Cdk4 inhibitor.