Proteins, introduction kinase

Signal transduction involves a transfer of information from cell surface receptors to the cytoplasm and ultimately to the nucleus where cellular activation and response are initated (1). Protein-tyrosine kinases (PTKs) serve central roles in many of these pathways by phosphorylating tyrosyl residues, which result in the introduction of phosphotyrosyl (pTyr, 1, Fig. 1) pharmacophores... 

The introduction of retro-, retro-inverso-, and PMRI-peptides with free and blocked C-and N-termini has been successful in numerous biological systems such as neurotransmitters, inhibitors of proteases and protein kinases, sweeteners, antimicrobial peptides, hormones, adhesion molecules, antigenic epitopes, immuno-modulators, and immunological probes. Table 1 provides an exhaustive list of retro-, retro-inverso-, PMRI-, and end-group-modified re/ro-mvmo-pseudopeptides derived from bioactive peptides. 

As mentioned in the introduction, CaMKKs can phosphorylate proteins in addition to CaMKI and CaMKIV. One such alternate target is the AMP-dependent protein kinase (AMPK) (Hawley et al., 1995 Hamilton et al., 2002), and recent studies present compelling evidence that CaMKKs are physiologically relevant activators of AMPK in cultured cells. These studies are of particular interest as AMPK is a kinase intimately involved in the regulation of metabolism, both at the cellular and organismal levels (Kemp et al., 1999). In mammals, AMPK has been implicated in diabetes, obesity and cardiovascular disease (Arad et al., 2002 Kemp et al., 2003) prompting a flurry of studies to identify the relevant AMPKK involved in each tissue that participates in the etiology of these diseases. 

CONTENTS Introduction to the Series An Editor s Foreword, Albert Padwa. Preface, Bruce E. Maryanoff and Cynthia A. Maryanoff. Computer Assisted Molecular Design Related to the Protein Kinase C Receptor, Paul A. Wenderand Cynthia M. Cribbs. Chemistry and Biology of the Immunosuppressant (-)-FK-506, Ichiro Shinkai and Nolan H. Sigal. The Development of Ketorolac Impact on Pyrrole Chemistry and on Pain Therapy, Joseph M. Muchowski. Application of Silicon Chemistry in the Corticosteroid Field, Douglas A. Livingston. Hu-perzine A-A Possible Lead Structure in the Treatment of Alzheimers Disease, Alan P. Kozikowski, X.C, Tang and Israel Hanin. Mechanism-Based-Dual-Action Cephalosporins, Harry A. Albrecht and James G. Christenson. Some Thoughts on Enzyme Inhibitors and the Quiescent Affinity Label Concept, Mien Krantz Index. 

Fig. 3.9 Compounds of the general structure 35 and the optimized structure 36 are protein kinase C (PKC) inhibitors. The introduction of an amide residue led to mixed PKC and bcr-abl kinase inhibitors 37, which lost their PKC-inhibitory activity by introduction of a...

Figure 2.19 The lead structure 67 is a protein kinase C (PKC) inhibitor prototype. Whereas the optimized analog 68 is a strong PKC inhibitor, amides 69 also inhibit tyrosine kinases like the bcr-abl kinase. Introduction of a methyl group, to form 70, abolishes the PKC activity. The optimized analog imatinib 71 (Gleevec , Glivec , Novartis) is a highly selective bcr-abl tyrosine kinase inhibitor.

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