Synthesis of the small peptide analogues of cyclin dependent kinase (CDK4) for cancer treatment

Abstract

Cyclin-dependent kinases (CDKs) are a group of enzymes that are involved in cell cycle progression regulation. The CDKs activate host proteins through phosphorylation on serine or threonine using adenosine triphosphate as a phosphate donor. Especially, cyclindependent kinase 4 (CDK4) has attracted much attention as a potential therapeutic target in treating cancer because it is the key player in the control of cell proliferation. Comparison of the best model of CDK4 with the structures of CDK6 and CDK2 is shown difference in the cyclin-binding region and in overall electrostatic potential. A partially hydrophobic, externalized loop structure present in CDK4, but absent in CDK2 and CDK6 is identified. The hypothesis is that should CDK4 be involved in binding to an additional unidentified protein partner, this fragment provides the most likely candidate for the binding site. This has led to the discovery of a peptide 1, N-Ac-L-Pro-L-Arg(H)-Gly-L-Pro-L-Arg(H)-L-Pro- NH2, from a previously uncharacterized structural domain on CDK4. In this work, solution phase peptide synthetic method is optimized and developed to synthesize linear peptide 64, N-Boc-L-Pro-L-Arg(NO2)-Gly-L-Pro-L-Arg(NO2)-L-Pro-OMe. A series of side chain modification peptides of compound 64 was synthesized and found that peptide 71, N-Ac-LPro- L-Arg(NO2)-Gly-L-Pro-L-Arg(NO2)-L-Pro-OMe had the most potent for anticancer activity. Therefore, alanine scanning compounds of hexapeptide 71 were synthesized by replacing each amino acid residue with L-alanine to investigate which amino acid residue had shown anticancer activity. Solid phase method was also optimized to synthesized peptide 1 and its alanine scanning compounds. To improve anticancer activity, cyclic peptides are synthesized by solution phase method. Biological assays were optimized. Clonogenic assay was chosen to test with our synthetic peptides against RT112 bladder cancer and MRC5-hTERT fibroblast cells

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