Rakesh K. Tiwari and Keykavous Parang Pages 2852 - 2866 ( 15 )
Protein kinases are enzymes that catalyze the transfer of the γ-phosphate group from ATP to the hydroxyl groups in side chains of tyrosine, serine, or threonine. Protein kinases are divided in two classes: tyrosine kinases (TKs) and serine/threonine kinases (STKs). Overexpression or activation of protein tyrosine kinases (PTKs) has been found to be responsible for the development of many diseases, including cancer, inflammation, and many cardiovascular and neurodegenerative disorders. Thus, the design of PTK inhibitors (PTKIs) has become a subject of a major interest for the pharmaceutical industry. A number of marketed PTKIs that target conserved ATP binding site of PTKs were found to demonstrate toxicity (e.g., imitanib and sorafenib) or to generate resistance (e.g., imitanib and vemurafenib in chronic myeloid leukemia and metastatic melanoma, respectively). Thus, alternative strategies are urgently required for designing novel PTKIs. Linear peptides designed based on the natural protein substrates of PTKs have been introduced to target unique and non conserved PTK regions, such as substrate binding site. These compounds are more specific than the small molecules that usually target conserved ATP binding site. On the other hand, linear peptides are susceptible to hydrolysis by endogenous peptidases. Cyclization of linear peptides has led to generation of diverse conformationally constrained structures as PTKIs. Introduction of the conformational constraints enhances the stability towards proteases, the free energy upon binding, and binding affinity, but reduces the conformational entropy penalty upon receptor binding. Herein, design strategies for conformationally constrained peptides and their application as PTKIs are discussed.
Cyclization, inhibitor, peptide, protein kinase, selectivity, SH2 domain, SH3 domain, tyrosine kinase, free energy, binding affinity
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