Development of a selective pseudosubstrate-based peptide inhibitor of pp60c-src protein tyrosine kinase |
| |
Authors: | Jinzi J Wu Hoang Phan Sydney E Salmon and Kit S Lam |
| |
Institution: | (1) Arizona Cancer Center, College of Medicine, University of Arizona, 1515 N. Campbell Avenue, 85724 Tucson, AZ, U.S.A.;(2) Department of Medicine, College of Medicine, University of Arizona, 1515 N. Campbell Avenue, 85724 Tucson, AZ, U.S.A.;(3) Selectide Corporation, a subsidiary of Hoechst Marion Roussel, Inc., 1580 E. Hanley Boulevard, 85737 Tucson, AZ, U.S.A.;(4) Department of Microbiology and Immunology, College of Medicine, University of Arizona, 85724 Tucson, AZ, U.S.A. |
| |
Abstract: | Summary Using a combinatorial peptide library method, we identified YIYGSFK as an efficient and specific peptide substrate for pp60c-src protein tyrosine kinase (PTK) Lam et al., Int. J. Pept. Protein Res., 45 (1995) 587]. Employing YIYGSFK as a template, we synthesized and evaluated a series of pseudosubstrate-based inhibitors for pp60c-src. We found that the efficiency of a given inhibitor was highly dependent on the specific tyrosine analog used at the phosphorylation site of the substrate. One of these pseudosubstrate inhibitors, YI(2-Nal)GSFK, selectively inhibited the kinase activity of pp60c-src, with a Ki of 24 M. This peptide inhibitor exhibited selectivity for pp60c-src as compared to other PTKs tested, such as c-Abl and Bcr-Abl. Our results suggest that selective inhibitors for a specific PTK can be developed when the structure of a specific and efficient small peptide substrate for this PTK can be used as a template for structure modification.Abbreviations 1-Nal
l-1-naphthylalanine
- 2-Nal
l-2-naphthylalanine
- BOP
benzotriazolyl-N-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate
- BSA
bovine serum albumin
- cAPK
cyclic AMP-dependent protein kinase
- DIEA
diisopropylethylamine
- EGFR
epidermal growth factor receptor
- Fmoc
fluorenylmethoxycarbonyl
- HOBt
1-hydroxybenzotriazole
- MES
2-N-morpholino]ethanesulfonic acid
- PBS
phosphate-buffered salts
- pCl
l-p-chlorophenylalanine
- pF
l-p-fluorophenylalanine
- PTK
protein tyrosine kinase
- TLC
thin-layer chromatography |
| |
Keywords: | Peptide substrate Pseudosubstrate inhibitor Kinetics Selectivity |
本文献已被 SpringerLink 等数据库收录! |
|