Inhibition of cancer cell growth by cyclin dependent kinase 4 inhibitors synthesized based on the structure of 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 (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.
Mahale
Sachin
S
Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UK.
Aubry
Carine
C
Jenkins
Paul R
PR
Maréchal
Jean-Didier
JD
Sutcliffe
Michael J
MJ
Chaudhuri
Bhabatosh
B
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004278:DNA, Superhelical / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004996:Ethidium / Q000737:chemistry; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D009690:Nucleic Acid Conformation; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines
D000970:Antineoplastic Agents; D051358:Cyclin-Dependent Kinase 4; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D004996:Ethidium; D007211:Indoles; D016160:Retinoblastoma Protein; C069346:fascaplysine; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines